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1
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Beilmann M, Adkins K, Boonen HCM, Hewitt P, Hu W, Mader R, Moore S, Rana P, Steger-Hartmann T, Villenave R, van Vleet T. Application of new approach methodologies for nonclinical safety assessment of drug candidates. Nat Rev Drug Discov 2025:10.1038/s41573-025-01182-9. [PMID: 40316753 DOI: 10.1038/s41573-025-01182-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2025] [Indexed: 05/04/2025]
Abstract
The development of new approach methodologies (NAMs) and advances with in vitro testing systems have prompted revisions in regulatory guidelines and inspired dedicated in vitro/ex vivo studies for nonclinical safety assessment. This Review by a safety reflection initiative subgroup of the European Federation of Pharmaceutical Industries and Associations (EFPIA)/Preclinical Development Expert Group (PDEG) summarizes the current state and potential application of in vitro studies using human-derived material for safety assessment in drug development. It focuses on case studies from recent projects in which animal models alone proved to be limited or inadequate for safety testing. It further highlights four categories of drug candidates for which alternative in vitro approaches are applicable and discusses progress in using in vitro testing solutions for safety assessment in these categories. Finally, the article highlights new risk assessment strategies, initiatives and consortia promoting the advancement of NAMs. This collective work is meant to encourage the use of NAMs for more human-relevant safety assessment, which should ultimately result in reduced animal testing for drug development.
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Affiliation(s)
- Mario Beilmann
- Global Nonclinical Safety & DMPK, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
| | | | | | - Philip Hewitt
- Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, Germany
| | - Wenyue Hu
- Vividion Therapeutics, San Diego, CA, USA
| | - Robert Mader
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Payal Rana
- Drug Safety R&D, Pfizer Inc., Groton, CT, USA
| | - Thomas Steger-Hartmann
- Research & Development, Pharmaceuticals, Preclinical Development, Bayer AG, Berlin, Germany
| | - Remi Villenave
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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2
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Sacco JJ, Kirk P, Leach E, Shoushtari AN, Carvajal RD, Britton-Rivet C, Khakoo S, Collins L, de la Cruz-Merino L, Eroglu Z, Ikeguchi AP, Nathan P, Hamid O, Butler MO, Stanhope S, Ranade K, Sato T. Evolution of the tumor immune landscape during treatment with tebentafusp, a T cell receptor-CD3 bispecific. Cell Rep Med 2025; 6:102076. [PMID: 40239619 PMCID: PMC12047528 DOI: 10.1016/j.xcrm.2025.102076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/08/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025]
Abstract
Metastatic uveal melanoma is an aggressive disease with poor outcome, which is refractory to immune checkpoint inhibitors. A T cell receptor (TCR)-based CD3 bispecific, tebentafusp, delivers clinical benefit in patients with metastatic uveal melanoma. Understanding the molecular basis for the anti-tumor activity of tebentafusp in an indication where checkpoint inhibitors are ineffective could aid in identification of other solid tumor indications where CD3 bispecifics may serve an unmet need. By analyzing tumor biopsies taken prior to treatment, early on-treatment, and at progression (NCT02570308), using RNA sequencing (RNA-seq) and immunohistochemistry (IHC), we show that expression of interferon-related genes in the tumor prior to treatment is associated with improved overall survival and tumor reduction on tebentafusp, that T cell recruitment occurs even in tumors with a low baseline level of T cell infiltration, and that durability of changes induced in the tumor microenvironment is key for survival duration.
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Affiliation(s)
- Joseph J Sacco
- Clatterbridge Cancer Center - NHS Foundation Trust, Wirral, UK; University of Liverpool, Liverpool, UK
| | | | | | - Alexander N Shoushtari
- Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
| | - Richard D Carvajal
- Northwell Health Cancer Institute, New Hyde Park, NY, USA; Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY, USA
| | | | | | | | - Luis de la Cruz-Merino
- Oncology Department, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | | | - Alexandra P Ikeguchi
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul Nathan
- Mount Vernon Cancer Centre, Northwood, UK; University College London Hospital, London, UK
| | - Omid Hamid
- The Angeles Clinical and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, CA, USA
| | - Marcus O Butler
- Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, Toronto, ON, Canada; Department of Medicine and Department of Immunology, University of Toronto, Toronto, ON, Canada
| | | | | | - Takami Sato
- Sidney Kimmel Cancer Center, Jefferson University, Philadelphia, PA, USA
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3
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Hassel JC, Stanhope S, Greenshields-Watson A, Machiraju D, Enk A, Holland C, Abdullah SE, Benlahrech A, Orloff M, Nathan P, Piperno-Neumann S, Staeger R, Dummer R, Meier-Schiesser B. Tebentafusp Induces a T-Cell-Driven Rash in Melanocyte-Bearing Skin as an Adverse Event Consistent with the Mechanism of Action. J Invest Dermatol 2025; 145:559-572.e9. [PMID: 39019150 DOI: 10.1016/j.jid.2024.03.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/07/2024] [Accepted: 03/18/2024] [Indexed: 07/19/2024]
Abstract
Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage-specific antigen gp100 on HLA-A∗02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator's choice (n = 126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced, and expression of melanocytic genes decreased, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival as patients without a rash in the phase 3 randomized trial IMCgp100-202 (hazard ratio = 0.84, 95% confidence interval = 0.53-1.32). In summary, skin rash is an off-tumor, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.
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Affiliation(s)
- Jessica C Hassel
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
| | | | | | - Devayani Machiraju
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Enk
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | | | | | | | - Marlana Orloff
- Sidney Kimmel Cancer Center, Jefferson University, Philadelphia, Pennsylvania, USA
| | - Paul Nathan
- Mount Vernon Cancer Centre, Northwood, United Kingdom
| | | | - Ramon Staeger
- Department of Dermatology, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland
| | - Barbara Meier-Schiesser
- Department of Dermatology, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland
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4
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Kulbay M, Tuli N, Mazza M, Jaffer A, Juntipwong S, Marcotte E, Tanya SM, Nguyen AXL, Burnier MN, Demirci H. Oncolytic Viruses and Immunotherapy for the Treatment of Uveal Melanoma and Retinoblastoma: The Current Landscape and Novel Advances. Biomedicines 2025; 13:108. [PMID: 39857692 PMCID: PMC11762644 DOI: 10.3390/biomedicines13010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 12/25/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities for UM and RB have been proposed, with chemotherapy for RB cases and plaque radiation therapy for localized UM as first-line treatment options. Extraocular extension, recurrence, and metastasis constitute the major challenges of conventional treatments. To overcome these obstacles, immunotherapy, which encompasses different treatment options such as oncolytic viruses, antibody-mediated immune modulations, and targeted immunotherapy, has shown great potential as a novel therapeutic tool for cancer therapy. These anti-cancer treatment options provide numerous advantages such as selective cancer cell death and the promotion of an anti-tumor immune response, and they prove useful in preventing vision impairment due to macular and/or optic disc involvement. Numerous factors such as the vector choice, route of administration, dosing, and patient characteristics must be considered when engineering an oncolytic virus or other forms of immunotherapy vectors. This manuscript provides an in-depth review of the molecular design of oncolytic viruses (e.g., virus capsid proteins and encapsulation technologies, vectors for delivery, cell targeting) and immunotherapy. The most recent advances in preclinical- and clinical-phase studies are further summarized. The recent developments in virus-like drug conjugates (i.e., AU011), oncolytic viruses for metastatic UM, and targeted immunotherapies have shown great results in clinical trials for the future clinical application of these novel technologies in the treatment algorithm of certain intraocular tumors.
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Affiliation(s)
- Merve Kulbay
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 3J1, Canada; (M.K.)
| | - Nicolas Tuli
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
| | - Massimo Mazza
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
| | - Armaan Jaffer
- Faculty of Health Sciences, Queen’s University, Kingston, ON K7L 2V5, Canada
- Research Excellence Cluster in Vision, University of British Columbia, Vancouver, BC V5Z 3N9, Canada
| | - Sarinee Juntipwong
- Kellogg Eye Center, Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, MI 48105, USA
| | - Emily Marcotte
- McGill University Ocular Pathology and Translational Research Laboratory, McGill University, Montreal, QC H4A 3J1, Canada;
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Stuti Misty Tanya
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 3J1, Canada; (M.K.)
| | - Anne Xuan-Lan Nguyen
- Department of Ophthalmology & Vision Sciences, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Miguel N. Burnier
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 3J1, Canada; (M.K.)
- McGill University Ocular Pathology and Translational Research Laboratory, McGill University, Montreal, QC H4A 3J1, Canada;
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Hakan Demirci
- Kellogg Eye Center, Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, MI 48105, USA
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5
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Murugesan G, Paterson RL, Kulkarni R, Ilkow V, Suckling RJ, Connolly MM, Karuppiah V, Pengelly R, Jadhav A, Donoso J, Heunis T, Bunjobpol W, Philips G, Ololade K, Kay D, Sarkar A, Barber C, Raj R, Perot C, Grant T, Treveil A, Walker A, Dembek M, Gibbs-Howe D, Hock M, Carreira RJ, Atkin KE, Dorrell L, Knox A, Leonard S, Salio M, Godinho LF. Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen. Nat Commun 2024; 15:10126. [PMID: 39578466 PMCID: PMC11584656 DOI: 10.1038/s41467-024-54378-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.
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Affiliation(s)
| | | | - Rakesh Kulkarni
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Veronica Ilkow
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Mary M Connolly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Robert Pengelly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Archana Jadhav
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Jose Donoso
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tiaan Heunis
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Gwilym Philips
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Kafayat Ololade
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Daniel Kay
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Anshuk Sarkar
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Claire Barber
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Ritu Raj
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Carole Perot
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tressan Grant
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Agatha Treveil
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Walker
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Marcin Dembek
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Dawn Gibbs-Howe
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Miriam Hock
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Kate E Atkin
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Lucy Dorrell
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Knox
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Sarah Leonard
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Mariolina Salio
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Luis F Godinho
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK.
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6
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van de Donk NW, Rasche L, Sidana S, Zweegman S, Garfall AL. T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma: Optimal Dosing Schedule and Duration of Treatment. Blood Cancer Discov 2024; 5:388-399. [PMID: 39321136 PMCID: PMC11528190 DOI: 10.1158/2643-3230.bcd-24-0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/22/2024] [Accepted: 09/11/2024] [Indexed: 09/27/2024] Open
Abstract
T cell-redirecting bispecific antibodies (BsAb) induce significant responses in heavily pretreated multiple myeloma. BsAbs are currently administered in a dose-dense manner until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy. Significance: There is increasing evidence that after initial debulking, less-frequent BsAb administration mitigates T-cell exhaustion and minimizes the potential for chronic or cumulative toxicity while maintaining durable clinical responses. In addition, specific patient subsets may experience an extended treatment-free period following fixed-duration treatment. Fixed-duration treatment may, therefore, decrease cumulative toxicities and the burden on patients and healthcare systems.
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Affiliation(s)
- Niels W.C.J. van de Donk
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - Leo Rasche
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Surbhi Sidana
- Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, California
| | - Sonja Zweegman
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - Alfred L. Garfall
- Division of Hematology and Oncology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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7
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Gu Y, Zhao Q. Clinical Progresses and Challenges of Bispecific Antibodies for the Treatment of Solid Tumors. Mol Diagn Ther 2024; 28:669-702. [PMID: 39172329 PMCID: PMC11512917 DOI: 10.1007/s40291-024-00734-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2024] [Indexed: 08/23/2024]
Abstract
In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy against tumors. BsAbs can recruit and activate immune cells, block multiple signaling pathways, and deliver therapeutic payloads directly to tumor sites. This review provides a comprehensive overview of the recent advances in the development and clinical application of BsAbs for the treatment of solid tumors. We discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in solid tumor therapy. Several studies have also analyzed the clinical progress of bispecific antibodies. However, this review distinguishes itself by exploring the challenges associated with bispecific antibodies and proposing potential solutions. As the field progresses, BsAbs hold promise to redefine cancer treatment paradigms and offer new hope to patients with solid tumors.
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Affiliation(s)
- Yuheng Gu
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China
| | - Qi Zhao
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China.
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8
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La Sorda M, De Lorenzis D, Battaglia A, Fiori B, Graffeo R, Santangelo R, D’Inzeo T, De Pascale G, Schinzari G, Pedone RR, Rossi E, Sanguinetti M, Sali M, Fattorossi A. A New Easy-to-Perform Flow Cytometry Assay for Determining Bacterial- and Viral-Infection-Induced Polymorphonuclear Neutrophil and Monocyte Membrane Marker Modulation in Febrile Patients. Int J Mol Sci 2024; 25:11632. [PMID: 39519183 PMCID: PMC11547050 DOI: 10.3390/ijms252111632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
We developed a flow cytometry (FC) assay enabling the rapid and accurate identification of bacterial and viral infections using whole blood samples. The streamlined flow cytometry assay is designed to be user-friendly, making it accessible even for operators with limited experience in FC techniques. The key components of the assay focus on the expression levels of specific surface markers-CD64 on polymorphonuclear neutrophils (PMN) as a marker for bacterial infection, and CD169 on monocytes (MO) for viral infection. The strong performance indicated by an area under the receiver operating characteristic (ROC) curve of 0.94 for both PMN CD64 positive predictive value (PPV) 97.96% and negative predictive value (NPV) 76.67%, and MO CD169 PPV 82.6% and NPV 86.9%, highlight the assay's robustness in differentiating between bacterial and viral infections accurately. The FC assay includes the assessment of immune system status through HLA-DR and IL-1R2 modulation in MO, providing a useful insight into the patients' immune response. The significant increase in the frequency of MO exhibiting reduced HLA-DR expression and elevated IL-1R2 levels in infected patients (compared to healthy controls) underscores the potential of these markers as indicators of infection severity. Although the overall correlation between HLA-DR and IL-1R2 expression levels was not significant across all patients, there was a trend in patients with more severe disease suggesting that these markers may have the potential to assist in stratifying patient risk. The present FC assay has the potential to become routine in the clinical microbiology laboratory community and to be helpful in guiding clinical decision making.
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Affiliation(s)
- Marilena La Sorda
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Desy De Lorenzis
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Alessandra Battaglia
- Department of Life Science and Public Health, Catholic University of the Sacred Heart, 00168 Rome, Italy;
| | - Barbara Fiori
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Rosalia Graffeo
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Rosaria Santangelo
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Tiziana D’Inzeo
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
| | - Gennaro De Pascale
- Emergency Department, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy;
| | - Giovanni Schinzari
- Medical Oncology, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (G.S.); (R.R.P.); (E.R.)
| | - Romina Rose Pedone
- Medical Oncology, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (G.S.); (R.R.P.); (E.R.)
| | - Ernesto Rossi
- Medical Oncology, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (G.S.); (R.R.P.); (E.R.)
| | - Maurizio Sanguinetti
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
- Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Michela Sali
- Department of Laboratory Sciences and Infectious Diseases, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy; (M.L.S.); (D.D.L.); (B.F.); (R.G.); (R.S.); (T.D.); (M.S.); (M.S.)
- Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Andrea Fattorossi
- Laboratory of Oncology and Flow Cytometry, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy
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9
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Anbari S, Wang H, Arulraj T, Nickaeen M, Pilvankar M, Wang J, Hansel S, Popel AS. Identifying biomarkers for treatment of uveal melanoma by T cell engager using a QSP model. NPJ Syst Biol Appl 2024; 10:108. [PMID: 39349498 PMCID: PMC11443075 DOI: 10.1038/s41540-024-00434-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 09/02/2024] [Indexed: 10/02/2024] Open
Abstract
Uveal melanoma (UM), the primary intraocular tumor in adults, arises from eye melanocytes and poses a significant threat to vision and health. Despite its rarity, UM is concerning due to its high potential for liver metastasis, resulting in a median survival of about a year after detection. Unlike cutaneous melanoma, UM responds poorly to immune checkpoint inhibition (ICI) due to its low tumor mutational burden and PD-1/PD-L1 expression. Tebentafusp, a bispecific T cell engager (TCE) approved for metastatic UM, showed potential in clinical trials, but the objective response rate remains modest. To enhance TCE efficacy, we explored quantitative systems pharmacology (QSP) modeling in this study. By integrating a TCE module into an existing QSP model and using clinical data on UM and tebentafusp, we aimed to identify and rank potential predictive biomarkers for patient selection. We selected 30 important predictive biomarkers, including model parameters and cell concentrations in tumor and blood compartments. We investigated biomarkers using different methods, including comparison of median levels in responders and non-responders, and a cutoff-based biomarker testing algorithm. CD8+ T cell density in the tumor and blood, CD8+ T cell to regulatory T cell ratio in the tumor, and naïve CD4+ density in the blood are examples of key biomarkers identified. Quantification of predictive power suggested a limited predictive power for single pre-treatment biomarkers, which was improved by early on-treatment biomarkers and combination of predictive biomarkers. Ultimately, this QSP model could facilitate biomarker-guided patient selection, improving clinical trial efficiency and UM treatment outcomes.
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Affiliation(s)
- Samira Anbari
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Hanwen Wang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Theinmozhi Arulraj
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Masoud Nickaeen
- Biotherapeutics Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Minu Pilvankar
- Biotherapeutics Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Jun Wang
- Biotherapeutics Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Steven Hansel
- Biotherapeutics Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, and the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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10
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Yao Z, Zeng Y, Liu C, Jin H, Wang H, Zhang Y, Ding C, Chen G, Wu D. Focusing on CD8 + T-cell phenotypes: improving solid tumor therapy. J Exp Clin Cancer Res 2024; 43:266. [PMID: 39342365 PMCID: PMC11437975 DOI: 10.1186/s13046-024-03195-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024] Open
Abstract
Vigorous CD8+ T cells play a crucial role in recognizing tumor cells and combating solid tumors. How T cells efficiently recognize and target tumor antigens, and how they maintain the activity in the "rejection" of solid tumor microenvironment, are major concerns. Recent advances in understanding of the immunological trajectory and lifespan of CD8+ T cells have provided guidance for the design of more optimal anti-tumor immunotherapy regimens. Here, we review the newly discovered methods to enhance the function of CD8+ T cells against solid tumors, focusing on optimizing T cell receptor (TCR) expression, improving antigen recognition by engineered T cells, enhancing signal transduction of the TCR-CD3 complex, inducing the homing of polyclonal functional T cells to tumors, reversing T cell exhaustion under chronic antigen stimulation, and reprogramming the energy and metabolic pathways of T cells. We also discuss how to participate in the epigenetic changes of CD8+ T cells to regulate two key indicators of anti-tumor responses, namely effectiveness and persistence.
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Affiliation(s)
- Zhouchi Yao
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yayun Zeng
- Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Cheng Liu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Huimin Jin
- Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hong Wang
- Department of Scientific Research, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Yue Zhang
- Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Chengming Ding
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Guodong Chen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Daichao Wu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
- Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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11
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Rus Bakarurraini NAA, Kamarudin AA, Jamal R, Abu N. Engineered T cells for Colorectal Cancer. Immunotherapy 2024; 16:987-998. [PMID: 39229803 PMCID: PMC11485792 DOI: 10.1080/1750743x.2024.2391733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 08/06/2024] [Indexed: 09/05/2024] Open
Abstract
Colorectal cancer (CRC) is a major contributor to global cancer incidence and mortality. Conventional treatments have limitations; hence, innovative approaches are imperative. Recent advancements in cancer research have led to the development of personalized targeted therapies and immunotherapies. Immunotherapy, in particular, T cell-based therapies, exhibited to be promising in enhancing cancer treatment outcomes. This review focuses on the landscape of engineered T cells as a potential option for the treatment of CRC. It highlights the approaches, challenges and current advancements in this field. As the understanding of molecular mechanisms increases, engineered T cells hold great potential in revolutionizing cancer treatment. To fully explore their safety efficacy in improving patient outcomes, further research and clinical trials are necessary.
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Affiliation(s)
| | - Ammar Akram Kamarudin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
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12
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Koch EAT, Heppt MV, Berking C. The Current State of Systemic Therapy of Metastatic Uveal Melanoma. Am J Clin Dermatol 2024; 25:691-700. [PMID: 38907174 PMCID: PMC11358228 DOI: 10.1007/s40257-024-00872-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2024] [Indexed: 06/23/2024]
Abstract
Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.
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Affiliation(s)
- Elias A T Koch
- Department of Dermatology, Deutsches Zentrum Immuntherapie (DZI), Bavarian Cancer Research Center (BZKF), Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), CCC Erlangen-EMN, 91054, Erlangen, Germany
| | - Markus V Heppt
- Department of Dermatology, Deutsches Zentrum Immuntherapie (DZI), Bavarian Cancer Research Center (BZKF), Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), CCC Erlangen-EMN, 91054, Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Deutsches Zentrum Immuntherapie (DZI), Bavarian Cancer Research Center (BZKF), Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), CCC Erlangen-EMN, 91054, Erlangen, Germany.
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13
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Paterson RL, La Manna MP, Arena De Souza V, Walker A, Gibbs-Howe D, Kulkarni R, Fergusson JR, Mulakkal NC, Monteiro M, Bunjobpol W, Dembek M, Martin-Urdiroz M, Grant T, Barber C, Garay-Baquero DJ, Tezera LB, Lowne D, Britton-Rivet C, Pengelly R, Chepisiuk N, Singh PK, Woon AP, Powlesland AS, McCully ML, Caccamo N, Salio M, Badami GD, Dorrell L, Knox A, Robinson R, Elkington P, Dieli F, Lepore M, Leonard S, Godinho LF. An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 2024; 121:e2318003121. [PMID: 38691588 PMCID: PMC11087797 DOI: 10.1073/pnas.2318003121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 03/08/2024] [Indexed: 05/03/2024] Open
Abstract
Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.
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Affiliation(s)
| | - Marco P. La Manna
- Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo90127, Italy
- Central Laboratory of Advanced Diagnosis and Biomedical Research, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, University of Palermo, Palermo90127, Italy
| | | | - Andrew Walker
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Dawn Gibbs-Howe
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Rakesh Kulkarni
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | | | - Mauro Monteiro
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | - Marcin Dembek
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | - Tressan Grant
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Claire Barber
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Diana J. Garay-Baquero
- National Institute for Health and Care Research, Biomedical Research Centre and Institute for Life Sciences, Faculty of Medicine, University of Southampton, SouthamptonSO16 6YD, United Kingdom
| | - Liku Bekele Tezera
- Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo90127, Italy
| | - David Lowne
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | - Robert Pengelly
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | | | - Amanda P. Woon
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | | | | | - Nadia Caccamo
- Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo90127, Italy
- Central Laboratory of Advanced Diagnosis and Biomedical Research, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, University of Palermo, Palermo90127, Italy
| | - Mariolina Salio
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Giusto Davide Badami
- Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo90127, Italy
- Central Laboratory of Advanced Diagnosis and Biomedical Research, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, University of Palermo, Palermo90127, Italy
| | - Lucy Dorrell
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Andrew Knox
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Ross Robinson
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Paul Elkington
- National Institute for Health and Care Research, Biomedical Research Centre and Institute for Life Sciences, Faculty of Medicine, University of Southampton, SouthamptonSO16 6YD, United Kingdom
| | - Francesco Dieli
- Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo90127, Italy
- Central Laboratory of Advanced Diagnosis and Biomedical Research, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, University of Palermo, Palermo90127, Italy
| | - Marco Lepore
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Sarah Leonard
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
| | - Luis F. Godinho
- Immunocore Ltd., Abingdon, OxfordshireOX14 4RY, United Kingdom
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14
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Cheng L, Chen L, Shi Y, Gu W, Ding W, Zheng X, Liu Y, Jiang J, Zheng Z. Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Mol Cancer 2024; 23:77. [PMID: 38627681 PMCID: PMC11020943 DOI: 10.1186/s12943-024-01956-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/07/2024] [Indexed: 04/19/2024] Open
Abstract
Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.
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Affiliation(s)
- Linyan Cheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute for Cell Therapy of Soochow University, Changzhou, China
| | - Yuan Shi
- Laboratory of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Weidong Ding
- Department of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Yan Liu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
| | - Jingting Jiang
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Zhuojun Zheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
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15
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Roshardt Prieto NM, Turko P, Zellweger C, Nguyen-Kim TDL, Staeger R, Bellini E, Levesque MP, Dummer R, Ramelyte E. Patterns of radiological response to tebentafusp in patients with metastatic uveal melanoma. Melanoma Res 2024; 34:166-174. [PMID: 38126339 PMCID: PMC10906186 DOI: 10.1097/cmr.0000000000000952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023]
Abstract
Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.
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Affiliation(s)
| | - Patrick Turko
- Department of Dermatology, University Hospital Zurich
- Medical Faculty, University of Zurich
| | - Caroline Zellweger
- Institute for Diagnostic and Interventional Radiology, University Hospital Zurich
| | - Thi Dan Linh Nguyen-Kim
- Institute for Diagnostic and Interventional Radiology, University Hospital Zurich
- Institute for Radiology and Nuclear Medicine Waid Municipal Hospital, Zurich, Switzerland
| | - Ramon Staeger
- Department of Dermatology, University Hospital Zurich
- Medical Faculty, University of Zurich
| | | | - Mitchell P. Levesque
- Department of Dermatology, University Hospital Zurich
- Medical Faculty, University of Zurich
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich
- Medical Faculty, University of Zurich
| | - Egle Ramelyte
- Department of Dermatology, University Hospital Zurich
- Medical Faculty, University of Zurich
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16
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Piulats JM, Watkins C, Costa-García M, Del Carpio L, Piperno-Neumann S, Rutkowski P, Hassel JC, Espinosa E, de la Cruz-Merino L, Ochsenreither S, Shoushtari AN, Orloff M, Salama AKS, Goodall HM, Baurain JF, Nathan P. Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis. Ann Oncol 2024; 35:317-326. [PMID: 38048850 DOI: 10.1016/j.annonc.2023.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/31/2023] [Accepted: 11/27/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.
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Affiliation(s)
- J M Piulats
- Institut Català d'Oncologia, Barcelona; Cancer Immunotherapy Group, OncoBell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - C Watkins
- Clarostat Consulting Ltd, Cheshire, UK
| | - M Costa-García
- Cancer Immunotherapy Group, OncoBell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona
| | - L Del Carpio
- Institut Català d'Oncologia, Barcelona; Cancer Immunotherapy Group, OncoBell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona
| | | | - P Rutkowski
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - J C Hassel
- University Hospital Heidelberg, Heidelberg, Germany
| | - E Espinosa
- Hospital Universitario La Paz, CIBERONC, Madrid
| | - L de la Cruz-Merino
- Oncology Department, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, Seville, Spain
| | | | - A N Shoushtari
- Memorial Sloan Kettering Cancer Center, New York; Weill Cornell Medical College, New York
| | - M Orloff
- Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia
| | | | | | - J-F Baurain
- Institut Roi Albert II Cliniques Universitaires St-Luc, UCLouvain, Brussels, Belgium
| | - P Nathan
- Mount Vernon Cancer Centre, Northwood, UK
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17
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Sorrentino FS, De Rosa F, Di Terlizzi P, Toneatto G, Gabai A, Finocchio L, Salati C, Spadea L, Zeppieri M. Uveal melanoma: Recent advances in immunotherapy. World J Clin Oncol 2024; 15:23-31. [PMID: 38292657 PMCID: PMC10823941 DOI: 10.5306/wjco.v15.i1.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/07/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, which is still characterized by poor prognosis. No standard therapeutic approaches for its prevention or treatment have been established. The application of immunotherapy agents, such as immune checkpoint inhibitors that are effective in cutaneous melanoma, has shown limited effects in the treatment of ocular disease. This is due to UM's distinct genetics, natural history, and complex interaction with the immune system. Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations, UMs are usually triggered by a mutation in GNAQ or GNA11. As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.
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Affiliation(s)
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Giacomo Toneatto
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Andrea Gabai
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Lucia Finocchio
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, “Sapienza” University of Rome, Rome 00142, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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18
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Al Balushi K, Al Hadhrami A, Balushi HA, Al Lawati A, Das S. Tebentafusp as a Promising Drug for the Treatment of Uveal Melanoma. Curr Drug Targets 2024; 25:149-157. [PMID: 38115619 DOI: 10.2174/0113894501280380231214105255] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 12/21/2023]
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and commonly occurs in the Caucasian population. The malignancy involves the uvea of the eye, which includes the iris, ciliary body, and choroid. The etiology of UM is still not well understood, but age is a risk factor. Symptoms include blurred vision, redness of the eye, floaters, dark spots, a change in the size of the pupil, and loss of vision. The location, shape, and size of the tumor are important for therapeutic purposes. Treating metastasis is always a challenge in UM cases. In cases of lung metastasis, the survival rate decreases. Treatment includes surgery, laser therapy, immunotherapy, hormone therapy, and chemotherapy. Recently, in 2022, the United States Food and Drug Administration (FDA) approved the drug tebentafusp. Tebentafusp was developed to target the most common HLA complex in humans. The present review discusses the indications for the use of a new drug tebentafusp, its mechanism of action, dose, pharmacokinetics, results of clinical trials conducted, and adverse effects like cytokine release syndrome. Hence, tebentafusp is the first T cell receptor (TCR) therapeutic drug that could be considered for the treatment of UM.
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Affiliation(s)
- Khalid Al Balushi
- Department of Medical, Sultan Qaboos University Hospital, Al Khoud, Muscat 123, Sultanate of Oman
| | - Abdulrahman Al Hadhrami
- Department of Medical, Sultan Qaboos University Hospital, Al Khoud, Muscat 123, Sultanate of Oman
| | - Hamdan Al Balushi
- Department of Medical, Sultan Qaboos University Hospital, Al Khoud, Muscat 123, Sultanate of Oman
| | - Abdullah Al Lawati
- Department of Medical, Sultan Qaboos University Hospital, Al Khoud, Muscat 123, Sultanate of Oman
| | - Srijit Das
- Department of Human & Clinical Anatomy, College of Medicine & Health Sciences, Sultan Qaboos University, Al Khoud, Muscat 123, Sultanate of Oman
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19
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Pang Z, Lu MM, Zhang Y, Gao Y, Bai JJ, Gu JY, Xie L, Wu WZ. Neoantigen-targeted TCR-engineered T cell immunotherapy: current advances and challenges. Biomark Res 2023; 11:104. [PMID: 38037114 PMCID: PMC10690996 DOI: 10.1186/s40364-023-00534-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/22/2023] [Indexed: 12/02/2023] Open
Abstract
Adoptive cell therapy using T cell receptor-engineered T cells (TCR-T) is a promising approach for cancer therapy with an expectation of no significant side effects. In the human body, mature T cells are armed with an incredible diversity of T cell receptors (TCRs) that theoretically react to the variety of random mutations generated by tumor cells. The outcomes, however, of current clinical trials using TCR-T cell therapies are not very successful especially involving solid tumors. The therapy still faces numerous challenges in the efficient screening of tumor-specific antigens and their cognate TCRs. In this review, we first introduce TCR structure-based antigen recognition and signaling, then describe recent advances in neoantigens and their specific TCR screening technologies, and finally summarize ongoing clinical trials of TCR-T therapies against neoantigens. More importantly, we also present the current challenges of TCR-T cell-based immunotherapies, e.g., the safety of viral vectors, the mismatch of T cell receptor, the impediment of suppressive tumor microenvironment. Finally, we highlight new insights and directions for personalized TCR-T therapy.
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Affiliation(s)
- Zhi Pang
- Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Man-Man Lu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China
| | - Yu Zhang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China
| | - Yuan Gao
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China
| | - Jin-Jin Bai
- Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jian-Ying Gu
- Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lu Xie
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China.
| | - Wei-Zhong Wu
- Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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20
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Wespiser M, Neidhardt E, Negrier S. Uveal melanoma: In the era of new treatments. Cancer Treat Rev 2023; 119:102599. [PMID: 37473516 DOI: 10.1016/j.ctrv.2023.102599] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023]
Abstract
Uveal melanoma (UM), also known as choroidal melanoma, is the leading adult intraocular tumor worldwide, affecting mainly Caucasian populations. The last decade has seen an improvement in the outcome of these tumors at the localized stage, in favor of conservative treatment of the eye, notably with new radioactive treatment techniques. Despite optimal management, half of the patients will become metastatic, with liver involvement in 90% of cases. The prognosis is pejorative and considers clinical, tumor anatomy, histological and molecular parameters. This review provides a broad overview of the different therapeutic options for the management of localized or metastatic UM disease, with recently updated data. Despite the known limited efficacy of chemotherapy and immune checkpoint inhibitors (ICI), we discuss the first results of combined immunotherapies, the arrival of a new first-in-class immunomodulatory treatment Tebentafusp, in HLA-A*02:01 patients, avenues of research into targeted anti-tyrosine kinase therapies, and the growing use of ctDNA to guide treatment prescription.
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Affiliation(s)
- M Wespiser
- Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
| | - E Neidhardt
- Centre Léon Bérard, University of Lyon, Lyon, France.
| | - S Negrier
- Centre Léon Bérard, University of Lyon, Lyon, France.
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21
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Hassel JC, Berking C, Forschner A, Gebhardt C, Heinzerling L, Meier F, Ochsenreither S, Siveke J, Hauschild A, Schadendorf D. Practical guidelines for the management of adverse events of the T cell engager bispecific tebentafusp. Eur J Cancer 2023; 191:112986. [PMID: 37595494 DOI: 10.1016/j.ejca.2023.112986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 08/20/2023]
Abstract
Tebentafusp is a new T cell receptor bispecific fusion protein and the first approved treatment option for human leucocyte antigen-A*02:01 (HLA-A*02:01) metastatic uveal melanoma, with a proven benefit in overall survival versus the investigator's choice. As a first-in-class therapeutic option, this Immune mobilising monoclonal T cell receptor Against Cancer (ImmTAC) is associated with a new adverse event (AE) profile. Based on clinical experience, a national expert group discussed recommendations for tebentafusp treatment, focusing on AE management. Further topics included prerequisites for initiating tebentafusp treatment, appropriate treatment setting, and patient selection criteria. To provide guidance for treating physicians, the resulting recommendations are summarised including a model standard operating procedure for AE management. Patients in good clinical condition and with a low tumour burden are good candidates for tebentafusp treatment, particularly if treated as early as possible after the diagnosis of metastatic disease. The safety profile of tebentafusp is manageable and includes two major pathologies: cytokine release syndrome (CRS) and skin-related events. Postdose monitoring should thus focus on pyrexia and hypotension as the first symptoms of cytokine release. To minimise the risk of hypotension associated with CRS, patients should receive intravenous fluids before starting treatment. The monitoring of liver values is crucial, as patients may experience an increase in transaminases, which can even manifest as tumour lysis syndrome.
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Affiliation(s)
- Jessica C Hassel
- Department of Dermatology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
| | - Carola Berking
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Ulmenweg 18, 91054 Erlangen, Germany
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstr. 25, 72076 Tuebingen, Germany
| | - Christoffer Gebhardt
- Department of Dermatology and Venereology, Skin Cancer Center, University Medical Center Hamburg-Eppendorf (UKE), Martinistr. 52, 20246 Hamburg, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstr. 9-11, 80337 Munich, Germany; Department of Dermatology, University Hospital Erlangen, 91054 Erlangen, Germany
| | - Friedegund Meier
- Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases and Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Sebastian Ochsenreither
- Department of Hematology, Oncology and Tumor Immunology, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Charité-Comprehensive Cancer Center, Charitéplatz 1, 10117 Berlin, Germany
| | - Jens Siveke
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Medicine Essen, Hufelandstr. 55, 45147 Essen, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Axel Hauschild
- Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Dirk Schadendorf
- Department of Dermatology, Comprehensive Cancer Center (Westdeutsches Tumorzentrum), German Cancer Consortium (DKTK, partner site Essen) and University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany
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22
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Tan Y, Lu Y, Chen S, Zou C, Qin B. Immunotherapy for ocular melanoma: a bibliometric and visualization analysis from 1991 to 2022. Front Oncol 2023; 13:1161759. [PMID: 37324010 PMCID: PMC10265996 DOI: 10.3389/fonc.2023.1161759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Background In recent years, new therapeutic options to overcome the mechanisms of tumor immune suppression be effective in the treatment of cutaneous melanoma. These approaches have also been applied in ocular melanoma. The aim of this study is to present the current status and research hotspots of immunotherapy for ocular melanoma from a bibliometric perspective and to explore the field of immunotherapy for malignant ocular melanoma research. Methods In this study, the Web of Science Core Collection database (WoSCC) and Pubmed were selected to search the literature related to immunotherapy of ocular melanoma. Using VOSviewer, CiteSpace, the R package "bibliometrix," and the bibliometric online platform through the construction and visualization of bibliometric networks, the country/region, institution, journal, author, and keywords were analyzed to predict the most recent trends in research pertaining to ocular melanoma and immunotherapy. Results A total of 401 papers and 144 reviews related to immunotherapy of ocular melanoma were included. The United States is the main driver of research in the field, ranking first in terms of the number of publications, total citations, and H-index. The UNIVERSITY OF TEXAS SYSTEM is the most active institution, contributing the most papers. Jager, Martine is the most prolific author, and Carvajal, Richard is the most frequently cited author. CANCERS is the most published journal in the field and J CLIN ONCOL is the most cited journal. In addition to ocular melanoma and immunotherapy, the most popular keywords were "uveal melanoma" and "targeted therapy". According to keyword co-occurrence and burst analysis, uveal melanoma, immunotherapy, melanoma, metastases, bap1, tebentafusp, bioinformatics, conjunctival melanoma, immune checkpoint inhibitors, ipilimumab, pembrolizumab, and other research topics appear to be at the forefront of this field's research and have the potential to remain a hot research topic in the future. Conclusion This is the first bibliometric study in the last 30 years to comprehensively map the knowledge structure and trends in the field of research related to ocular melanoma and immunotherapy. The results comprehensively summarize and identify research frontiers for scholars studying immunotherapy associated with ocular melanoma.
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Affiliation(s)
- Yao Tan
- Shenzhen Aier Eye Hospital, Aier Eye Hospital, Jinan University, Shenzhen, China
| | - Yijie Lu
- Shenzhen Aier Eye Hospital, Aier Eye Hospital, Jinan University, Shenzhen, China
| | - Sheng Chen
- Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Hospital of Jinan University, Shenzhen, China
| | - Chang Zou
- Shenzhen Aier Eye Hospital, Aier Eye Hospital, Jinan University, Shenzhen, China
- Shenzhen Aier Ophthalmic Technology Institute, Shenzhen, China
- School of Life and Health Sciences, The Chinese University of Kong Hong, Shenzhen, Guangdong, China
| | - Bo Qin
- Shenzhen Aier Eye Hospital, Aier Eye Hospital, Jinan University, Shenzhen, China
- Shenzhen Aier Ophthalmic Technology Institute, Shenzhen, China
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23
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Petzold A, Steeb T, Wessely A, Koch EAT, Vera J, Berking C, Heppt MV. Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment. Cancer Treat Rev 2023; 115:102543. [PMID: 36931146 DOI: 10.1016/j.ctrv.2023.102543] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023]
Abstract
BACKGROUND Distinct systemic treatments exist for metastatic uveal melanoma. Tebentafusp and combined immune checkpoint blockade (ICB) with ipilimumab plus anti-PD-1 antibodies are the most commonly used treatment options but their comparative efficacy is unclear. The aim of this study is to compare currently available systemic treatments regarding overall survival (OS) and progression-free survival (PFS) with a focus on the comparison of tebentafusp versus combined ICB. METHODS The protocol for this study was defined a priori and registered online in the PROSPERO international prospective register of systematic reviews (CRD42022308356, date of registration: 7.2.2022). We performed a systematic literature search in Medline, Embase, and Central to identify eligible studies reporting Kaplan-Meier curves or individual-level survival data showing OS and PFS for metastatic uveal melanoma patients treated with systemic treatments. Kaplan-Meier curves were digitized using the "WebPlotDigitizer" program. Individual-level survival data were subsequently remodelled and pooled for distinct treatment groups. To compare the OS of tebentafusp versus combined ICB, we used matching-adjusted indirect comparison (MAIC), two-stage MAIC (2SMAIC), and simulated treatment comparison (STC) together with digitized individual-level survival data as population-adjusted models. RESULTS Overall, 55 independent studies were included of which 2,682 patients were evaluable for OS and 2,258 for PFS. Tebentafusp showed the highest median OS (mOS) of 22.4 months (95% confidence interval (CI): 19.9-29.6) compared to combined ICB (mOS: 15.7 months (95% CI: 14.4-17.9)), anti-PD-(L)1 antibody (mOS: 10.9 months (95% CI: 9.8-13.4)), chemotherapy (mOS: 9.95 months (95% CI: 8.9-11.2)), targeted therapies (mOS: 8.86 months (95% CI: 7.5-10.8)), and anti-CTLA-4 antibody (mOS: 7.8 months (95% CI: 6.8-9.3). The median PFS (mPFS) was similar among the treatment groups ranging from 2.7 months to 3.4 months. For the comparison of tebentafusp versus combined ICB, the hazard ratio (HR) was 0.641 (95% CI: 0.449-0.915) in the unadjusted model, whereas the population-adjusted models showed a HR of 0.386 (95% CI: 0.236-0.631) using MAIC, 0.378 (95% CI: 0.234-0.612) applying 2SMAIC and 0.284 (95% CI: 0.184-0.440) using STC. CONCLUSIONS Tebentafusp achieved the best results compared to combined ICB and other systemic treatments, although these results have to be interpreted with caution due to the approximative methodical approach and high heterogeneity of included studies.
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Affiliation(s)
- Anne Petzold
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Theresa Steeb
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Anja Wessely
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Elias A T Koch
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Julio Vera
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Carola Berking
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
| | - Markus V Heppt
- Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Erlangen, Germany.
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Montazeri K, Pattanayak V, Sullivan RJ. Tebentafusp in the Treatment of Metastatic Uveal Melanoma: Patient Selection and Special Considerations. Drug Des Devel Ther 2023; 17:333-339. [PMID: 36785760 PMCID: PMC9921510 DOI: 10.2147/dddt.s368954] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/10/2023] [Indexed: 02/08/2023] Open
Abstract
Uveal melanoma (UM) is a rare type of melanoma with distinct features from cutaneous melanoma, low response rates to immune checkpoint inhibition, and poor survival rates. Tebentafusp, a bispecific antibody engaging T cells with gp 100 on HLA-A*02:01, was recently approved by the FDA as the first drug of its class and the first treatment approved by the FDA to treat UM. In this review, we summarize the preclinical and clinical data on tebentafusp for UM. We additionally discuss patient selection and the relevant challenges. For the literature search, PubMed search and relevant articles presented at international conferences were used.
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Affiliation(s)
- Kamaneh Montazeri
- Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Vikram Pattanayak
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Ryan J Sullivan
- Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA
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25
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Brentville VA, Symonds P, Chua J, Skinner A, Daniels I, Cook KW, Koncarevic S, Martinez-Pinna R, Shah S, Choudhury RH, Vaghela P, Weston D, Al-Omari A, Davis J, Durrant LG. Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy. Front Immunol 2022; 13:1066185. [PMID: 36544781 PMCID: PMC9760948 DOI: 10.3389/fimmu.2022.1066185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction Post translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. Methods A citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model. Results We show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide. Conclusion We propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.
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Affiliation(s)
- Victoria Anne Brentville
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,*Correspondence: Victoria Anne Brentville,
| | - Peter Symonds
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - JiaXin Chua
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Anne Skinner
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Ian Daniels
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Katherine Wendy Cook
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Sasa Koncarevic
- Proteome Sciences R & D GmbH & Co.KG, Frankfurt-am-Main, Germany
| | | | - Sabaria Shah
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Ruhul Hasan Choudhury
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Poonam Vaghela
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Daisy Weston
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Abdullah Al-Omari
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - James Davis
- Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
| | - Lindy G. Durrant
- Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
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26
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Chen LN, Carvajal RD. Tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. Expert Rev Anticancer Ther 2022; 22:1017-1027. [PMID: 36102132 PMCID: PMC10184536 DOI: 10.1080/14737140.2022.2124971] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/20/2022] [Accepted: 09/12/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal melanoma. AREAS COVERED In this review, we describe the mechanism of action of tebentafusp as well as preclinical data showing high tumor specificity of the drug. We also review promising early-phase trials in which tebentafusp demonstrated activity in metastatic uveal melanoma patients with an acceptable toxicity profile that included cytokine-mediated, dermatologic-related, and liver-related adverse events. Finally, we summarize findings from a pivotal phase III randomized trial in which tebentafusp demonstrated significant improvement in overall survival in comparison with investigator choice therapy. EXPERT OPINION Tebentafusp has transformed the treatment paradigm for metastatic uveal melanoma and should be the preferred frontline agent for most HLA-A*0201 positive patients. However, patients with rapidly progressing disease or high tumor benefit may not derive the same benefit. Areas of future study should focus on its role in the adjuvant setting as well as strategies to improve the efficacy of tebentafusp in the metastatic setting.
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Affiliation(s)
- Lanyi Nora Chen
- Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY 10032
| | - Richard D. Carvajal
- Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY 10032
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Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours. Nat Commun 2022; 13:5265. [PMID: 36071036 PMCID: PMC9452528 DOI: 10.1038/s41467-022-32952-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/25/2022] [Indexed: 11/08/2022] Open
Abstract
Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours.
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Wallace Z, Singh PK, Dorrell L. Combination strategies to durably suppress HIV-1: Soluble T cell receptors. J Virus Erad 2022; 8:100082. [PMID: 36065296 PMCID: PMC9440443 DOI: 10.1016/j.jve.2022.100082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/06/2022] [Accepted: 08/18/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapeutic interventions to enhance natural HIV-specific CD8+ T cell responses, such as vaccination or adoptive T cell transfer, have been a major focus of HIV cure efforts. However, these approaches have not been effective in overcoming viral immune evasion mechanisms. Soluble T cell receptor (TCR) bispecifics are a new class of 'off-the-shelf' therapeutic designed to address these limitations. These biologics are built on the Immune mobilising monoclonal TCRs against X disease (ImmTAX) platform, which was pioneered in oncology and recently validated by the FDA's approval of tebentafusp for treatment of metastatic uveal melanoma. ImmTAV® are an application of this technology undergoing clinical development for the elimination of chronic viral infections. ImmTAV molecules comprise an affinity-enhanced virus-specific TCR fused to an anti-CD3 effector domain. Engineering of the TCR confers extraordinary specificity and affinity for cognate viral antigen and the anti-CD3 enables retargeting of non-exhausted cytolytic T cells, irrespective of their specificity. These features enable ImmTAV molecules to detect and kill infected cells, even when expressing very low levels of antigen, bypassing ineffective host immune responses. Furthermore, the modularity of the platform allows for engineering of TCRs that effectively target viral variants. In this review, we discuss the progress made in the development of ImmTAV molecules as therapeutics for functional cure of chronic hepatitis B and HIV, from concept to the clinic.
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Carvajal RD, Nathan P, Sacco JJ, Orloff M, Hernandez-Aya LF, Yang J, Luke JJ, Butler MO, Stanhope S, Collins L, McAlpine C, Holland C, Abdullah SE, Sato T. Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma. J Clin Oncol 2022; 40:1939-1948. [PMID: 35254876 PMCID: PMC9177239 DOI: 10.1200/jco.21.01805] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 11/29/2021] [Accepted: 01/26/2022] [Indexed: 12/20/2022] Open
Abstract
PURPOSE This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM). METHODS In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017. RESULTS Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators. CONCLUSION Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.
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Affiliation(s)
- Richard D. Carvajal
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Paul Nathan
- Department of Medical Oncology, Mount Vernon Cancer Centre, London, United Kingdom
| | - Joseph J. Sacco
- Clatterbridge Cancer Centre, Bebington, United Kingdom
- University of Liverpool, Liverpool, United Kingdom
| | - Marlana Orloff
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
| | | | - Jessica Yang
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Jason J. Luke
- University of Chicago, Chicago, IL
- UPMC/University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA
| | | | | | | | | | | | | | - Takami Sato
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
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Song L, Liu S, Zhao S. Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway. Bioengineered 2022; 13:11240-11257. [PMID: 35485300 PMCID: PMC9208494 DOI: 10.1080/21655979.2022.2064205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.
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Affiliation(s)
- Lili Song
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shikai Liu
- Department of Obstetrics and Gynecology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Sufen Zhao
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Xu G, Luo Y, Wang H, Wang Y, Liu B, Wei J. Therapeutic bispecific antibodies against intracellular tumor antigens. Cancer Lett 2022; 538:215699. [PMID: 35487312 DOI: 10.1016/j.canlet.2022.215699] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 12/16/2022]
Abstract
Bispecific antibodies (BsAbs)-based therapeutics have been identified to be one of the most promising immunotherapy strategies. However, their target repertoire is mainly restricted to cell surface antigens rather than intracellular antigens, resulting in a relatively limited scope of applications. Intracellular tumor antigens are identified to account for a large proportion of tumor antigen profiles. Recently, bsAbs that target intracellular oncoproteins have raised much attention, broadening the targeting scope of tumor antigens and improving the efficacy of traditional antibody-based therapeutics. Consequently, this review will focus on this emerging field and discuss related research advances. We introduce the classification, characteristics, and clinical applications of bsAbs, the theoretical basis for targeting intracellular antigens, delivery systems of bsAbs, and the latest preclinical and clinical advances of bsAbs targeting several intracellular oncotargets, including those of cancer-testis antigens, differentiation antigens, neoantigens, and other antigens. Moreover, we summarize the limitations of current bsAbs, and propose several potential strategies against immune escape and T cell exhaustion as well as some future perspectives.
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Affiliation(s)
- Guanghui Xu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Yuting Luo
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Hanbing Wang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Yue Wang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Baorui Liu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Jia Wei
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China; Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210008, China.
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Abstract
Tebentafusp (tebentafusp-tebn; Kimmtrak®) is a first-in-class, bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor (TCR) CD3 T cell engager being developed by Immunocore for the treatment of uveal melanoma and malignant melanoma. The TCR arm of tebentafusp binds to HLA-A*02:01-positive uveal melanoma cells and activates polyclonal T cells, through CD3, to release inflammatory cytokines and cytolytic proteins, resulting in the direct lysis of tumour cells. In January 2022, tebentafusp received its first approval in the USA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma, and in February 2022 received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the treatment of uveal melanoma. Tebentafusp is under regulatory review for the treatment of metastatic uveal melanoma in the UK, Australia and Canada. Clinical studies of tebentafusp are underway for uveal melanoma and cutaneous melanoma in several countries worldwide. This article summarizes the milestones in the development of tebentafusp leading to this first approval for unresectable or metastatic uveal melanoma.
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Affiliation(s)
- Sohita Dhillon
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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Strobel SB, Machiraju D, Hassel JC. TCR-Directed Therapy in the Treatment of Metastatic Uveal Melanoma. Cancers (Basel) 2022; 14:1215. [PMID: 35267523 PMCID: PMC8909175 DOI: 10.3390/cancers14051215] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/11/2022] Open
Abstract
Metastatic uveal melanoma (mUM) is one of the most rapidly progressing tumors, with a bad prognosis and no standard-of-care treatment. Immune checkpoint inhibitors have revolutionized cancer therapy and improved overall survival in patients with metastatic cutaneous melanoma (mCM). However, this approach has been largely unimpressive, with no significant impact on the survival of mUM patients. Technical advances in immunotherapies have led to the development of novel T cell receptor (TCR)-based approaches to fight cancer. For the first time in over 50 years, compelling evidence demonstrates the power of TCR-based approaches for survival in mUM patients. Hence, this review summarizes novel TCR-based immunotherapeutic strategies currently in clinical studies for mUM treatment. We also discuss the potential combinational treatments to these strategies to maximize the clinical benefits.
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Affiliation(s)
| | | | - Jessica C. Hassel
- Department of Dermatology, National Center for Tumor Diseases, University Hospital Heidelberg, Code, 69120 Heidelberg, Germany; (S.B.S.); (D.M.)
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Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, Chen S, Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther 2022; 7:39. [PMID: 35132063 PMCID: PMC8821599 DOI: 10.1038/s41392-021-00868-x] [Citation(s) in RCA: 240] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex tumor environment. In this review, we summarize antibodies of various molecular types, antibody applications in cancer therapy, and details of clinical study advances. We also discuss the rationale and mechanism of action of various antibody formats, including antibody-drug conjugates, antibody-oligonucleotide conjugates, bispecific/multispecific antibodies, immunocytokines, antibody fragments, and scaffold proteins. With advances in modern biotechnology, well-designed novel antibodies are finally paving the way for successful treatments of various cancers, including precise tumor immunotherapy, in the clinic.
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Affiliation(s)
- Shijie Jin
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yanping Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xiao Liang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xinyu Gu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Jiangtao Ning
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yingchun Xu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Shuqing Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- Department of Precision Medicine on Tumor Therapeutics, ZJU-Hangzhou Global Scientific and Technological Innovation Center, 311200, Hangzhou, China.
| | - Liqiang Pan
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
- Key Laboratory of Pancreatic Disease of Zhejiang Province, 310003, Hangzhou, China.
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35
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Liu AW, Wei AZ, Maniar AB, Carvajal RD. Tebentafusp in Advanced Uveal Melanoma: Proof of Principal for the Efficacy of T-Cell Receptor Therapeutics and Bispecifics in Solid Tumors. Expert Opin Biol Ther 2022; 22:997-1004. [DOI: 10.1080/14712598.2022.2031970] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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36
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Carvajal RD, Butler MO, Shoushtari AN, Hassel JC, Ikeguchi A, Hernandez-Aya L, Nathan P, Hamid O, Piulats JM, Rioth M, Johnson DB, Luke JJ, Espinosa E, Leyvraz S, Collins L, Goodall HM, Ranade K, Holland C, Abdullah SE, Sacco JJ, Sato T. Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial. Nat Med 2022; 28:2364-2373. [PMID: 36229663 PMCID: PMC9671803 DOI: 10.1038/s41591-022-02015-7] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/16/2022] [Indexed: 01/21/2023]
Abstract
In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.
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Affiliation(s)
- Richard D. Carvajal
- grid.21729.3f0000000419368729Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY USA
| | - Marcus O. Butler
- grid.17063.330000 0001 2157 2938Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario Canada
| | - Alexander N. Shoushtari
- grid.51462.340000 0001 2171 9952Memorial Sloan Kettering Cancer Center, New York, NY USA ,grid.5386.8000000041936877XWeill Cornell Medical College, New York, NY USA
| | - Jessica C. Hassel
- grid.5253.10000 0001 0328 4908University Hospital Heidelberg, Heidelberg, Germany
| | - Alexandra Ikeguchi
- grid.266900.b0000 0004 0447 0018Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK USA
| | - Leonel Hernandez-Aya
- grid.4367.60000 0001 2355 7002Washington University School of Medicine, Saint Louis, MO USA
| | - Paul Nathan
- Mount Vernon Cancer Centre – East and North Herts NHS Trust, Northwood, Middlesex UK
| | - Omid Hamid
- grid.488730.0The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, CA USA
| | - Josep M. Piulats
- grid.417656.7Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), Hospitalet de Llobregat, Barcelona, Spain
| | - Matthew Rioth
- grid.430503.10000 0001 0703 675XUC Cancer Center, University of Colorado, Aurora, CO USA
| | - Douglas B. Johnson
- grid.412807.80000 0004 1936 9916Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN USA
| | - Jason J. Luke
- grid.21925.3d0000 0004 1936 9000UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA USA
| | - Enrique Espinosa
- grid.81821.320000 0000 8970 9163Hospital Universitario La Paz – CIBERONC, Madrid, Spain
| | - Serge Leyvraz
- grid.6363.00000 0001 2218 4662Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Laura Collins
- grid.450850.c0000 0004 0485 7917Immunocore, Abingdon-on-Thames, UK
| | | | | | | | | | - Joseph J. Sacco
- Clatterbridge Cancer Center – NHS Foundation Trust, Wirral, UK ,grid.10025.360000 0004 1936 8470University of Liverpool, Liverpool, UK
| | - Takami Sato
- grid.265008.90000 0001 2166 5843Sidney Kimmel Cancer Center, Jefferson University, Philadelphia, PA USA
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Gp-100 as a Novel Therapeutic Target in Uveal Melanoma. Cancers (Basel) 2021; 13:cancers13235968. [PMID: 34885078 PMCID: PMC8656894 DOI: 10.3390/cancers13235968] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 02/03/2023] Open
Abstract
Simple Summary Glycoprotein 100 (Gp-100) is a protein highly expressed in melanoma tissue that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. Abstract Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.
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Gerard CL, Delyon J, Wicky A, Homicsko K, Cuendet MA, Michielin O. Turning tumors from cold to inflamed to improve immunotherapy response. Cancer Treat Rev 2021; 101:102227. [PMID: 34656019 DOI: 10.1016/j.ctrv.2021.102227] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/30/2022]
Abstract
Immune checkpoint inhibitors have revolutionized the treatment landscape for a number of cancers over the last few decades. Nevertheless, a majority of patients still do not benefit from these treatments. Such patient-specific lack of response can be predicted, in part, from the immune phenotypes present in the tumor microenvironment. We provide a perspective on options to reprogram the tumors and their microenvironment to increase the therapeutic efficacy of immunotherapies and expand their efficacy against cold tumors. Additionally, we review data from current preclinical and clinical trials aimed at testing the different therapeutic options in monotherapy or preferably in combination with checkpoint inhibitors.
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Affiliation(s)
- C L Gerard
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland
| | - J Delyon
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland
| | - A Wicky
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland
| | - K Homicsko
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Michel A Cuendet
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland; Molecular Modelling Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Physiology and Biophysics, Weill Cornell Medicine, NY, USA.
| | - O Michielin
- Precision Oncology Center, Lausanne University Hospital (CHUV), Switzerland; Molecular Modelling Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, Joshua AM, Sacco JJ, Shoushtari AN, Orloff M, Piulats JM, Milhem M, Salama AKS, Curti B, Demidov L, Gastaud L, Mauch C, Yushak M, Carvajal RD, Hamid O, Abdullah SE, Holland C, Goodall H, Piperno-Neumann S. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med 2021; 385:1196-1206. [PMID: 34551229 DOI: 10.1056/nejmoa2103485] [Citation(s) in RCA: 512] [Impact Index Per Article: 128.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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Affiliation(s)
- Paul Nathan
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Jessica C Hassel
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Piotr Rutkowski
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Jean-Francois Baurain
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Marcus O Butler
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Max Schlaak
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Ryan J Sullivan
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Sebastian Ochsenreither
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Reinhard Dummer
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - John M Kirkwood
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Anthony M Joshua
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Joseph J Sacco
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Alexander N Shoushtari
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Marlana Orloff
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Josep M Piulats
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Mohammed Milhem
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - April K S Salama
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Brendan Curti
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Lev Demidov
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Lauris Gastaud
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Cornelia Mauch
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Melinda Yushak
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Richard D Carvajal
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Omid Hamid
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Shaad E Abdullah
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Chris Holland
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Howard Goodall
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
| | - Sophie Piperno-Neumann
- From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.)
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Abstract
PURPOSE OF REVIEW For patients with metastatic melanoma, immune checkpoint inhibition has drastically changed outcomes. Here, we review the current and next generations of immune-based anti-cancer therapeutics for patients with metastatic melanoma. RECENT FINDINGS The need for new anti-cancer therapeutics in patients with metastatic melanoma who have progression of disease despite immune checkpoint blockade is evident. Several novel agents are expected to have FDA approval within the next few years, as they have yielded impressive responses. Despite these optimistic agents, the field of immuno-oncology continues to expand and produce agents with novel mechanisms of action. The next generation of immunotherapy is based upon years of thoroughly researched immuno-oncology. Many of these agents are currently being evaluated in early phase clinical trials, and much of the preliminary data looks promising.
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Affiliation(s)
- Tyler Buchanan
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Afsaneh Amouzegar
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jason J Luke
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Hillman Cancer Center, UPMC, 5150 Centre Ave. Room 564, Pittsburgh, PA, 15232, USA.
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Orloff M. Clinical Trials in Metastatic Uveal Melanoma: Immunotherapy. Ocul Oncol Pathol 2021; 7:168-176. [PMID: 34307327 PMCID: PMC8280448 DOI: 10.1159/000513336] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Uveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM. SUMMARY This review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms "uveal melanoma" and "ocular melanoma," excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM. KEY MESSAGES There is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design.
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Affiliation(s)
- Marlana Orloff
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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42
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Abstract
Retinoblastoma in children and uveal melanoma in adults can pose a serious threat to both vision and life. For many decades, enucleation was often the only option to treat these intraocular malignancies. For retinoblastoma, intra-arterial chemotherapy is often utilized as the primary treatment at advanced academic centers and has dramatically improved local tumor control and eye salvage rates. For uveal melanoma, both plaque brachytherapy and proton beam irradiation have served as widely utilized therapies with a local failure rate of approximately 1–10%, depending on the series. Major recent advancements have allowed for a better understanding of the genomics of uveal melanoma and the impact of certain mutations on metastatic susceptibility. Gene expression profile stratifies uveal melanomas into two classes: low-risk (class 1) and high-risk (class 2). A loss-of-function mutation of BAP1 is associated with a class 2 gene expression profile and therefore confers worse prognosis due to elevated risk of metastasis. On the other hand, gain-of-function mutations of EIF1AX and SF3B1 correspond to a gene expression profile of class 1A and class 1B and confer a better prognosis. Preferentially expressed antigen in melanoma (PRAME) is an antigen that increases metastatic susceptibility when expressed in uveal melanoma cells. In addition to plaque brachytherapy and proton beam irradiation, both of which have demonstrated superb clinical outcomes, scientists are actively investigating newer therapeutic modalities as either primary therapy or adjuvant treatment, including a novel nanoparticle therapy and immunotherapy.
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Affiliation(s)
- Amy C Schefler
- Retina Consultants of Texas, Houston, Texas, USA
- Blanton Eye Institute, Houston, Texas, USA
| | - Ryan S Kim
- Retina Consultants of Texas, Houston, Texas, USA
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
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43
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Zhao Q, Jiang Y, Xiang S, Kaboli PJ, Shen J, Zhao Y, Wu X, Du F, Li M, Cho CH, Li J, Wen Q, Liu T, Yi T, Xiao Z. Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol 2021; 12:658753. [PMID: 33859650 PMCID: PMC8042275 DOI: 10.3389/fimmu.2021.658753] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/02/2021] [Indexed: 12/24/2022] Open
Abstract
This review provides insight into the role of engineered T-cell receptors (TCRs) in immunotherapy. Novel approaches have been developed to boost anticancer immune system, including targeting new antigens, manufacturing new engineered or modified TCRs, and creating a safety switch for endo-suicide genes. In order to re-activate T cells against tumors, immune-mobilizing monoclonal TCRs against cancer (ImmTAC) have been developed as a novel class of manufactured molecules which are bispecific and recognize both cancer and T cells. The TCRs target special antigens such as NY-ESO-1, AHNAKS2580F or ERBB2H473Y to boost the efficacy of anticancer immunotherapy. The safety of genetically modified T cells is very important. Therefore, this review discusses pros and cons of different approaches, such as ImmTAC, Herpes simplex virus thymidine kinase (HSV-TK), and inducible caspase-9 in cancer immunotherapy. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. New approaches that can better detect antigens and drive an effective T cell response are discussed as well.
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Affiliation(s)
- Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Yu Jiang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shixin Xiang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Parham Jabbarzadeh Kaboli
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tao Liu
- Department of Oncology Rehabilitation, Shenzhen Luohu People's Hospital, Shenzhen, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Ma J, Yang Y, Wang L, Jia X, Lu T, Zeng Y, Liu L, Gao Y. Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer. Aging (Albany NY) 2021; 13:7211-7227. [PMID: 33639614 PMCID: PMC7993667 DOI: 10.18632/aging.202579] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/19/2020] [Indexed: 12/19/2022]
Abstract
Our study aims to detect the underlying mechanism of the suppressive effect of Follistatin-like 1 (FSTL1) on lung metastasis of triple negative breast cancer (TNBC). We found that FSTL1 had no effect on the proliferation and metastasis of 4T1 cells in vitro, while in the tumor-bearing Fstl1 heterozygous (Fstl1+/-) mice, the number of anti-tumor T lymphocytes in the lung was significantly reduced with the increase in lung metastasis. Impaired development of T cells can cause dysfunction of adaptive immune system, which promotes cancer metastasis. Therefore the effect of FSTL1 on T cell development was further investigated. Lower population of T cells in periphery and decreased proliferation of CD4- CD8- double negative (DN) thymocytes and impairment development of T cells were found in Fstl1+/- mice. Furthermore, high expression of FSTL1 in medullary thymus epithelial (mTEC) cells and decreased mRNA expression of inducible costimulator on activated T-cell ligand (Icosl) in mTECsh Fstl1 were detected. Combining other studies that the generation of ICOSL by mTEC cells promotes CD4+ single positive (SP) thymocytes to produce IL-2, which promotes T cell development. Our results indicate FSTL1 deficiency in mTEC cells impairs T cell development to promote the lung metastasis of TNBC.
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Affiliation(s)
- Jie Ma
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Ying Yang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lulu Wang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaowei Jia
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Tao Lu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yiyan Zeng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Li Liu
- Department of Experimental Center for Basic Medical Teaching, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yan Gao
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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45
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Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires. Int J Mol Sci 2021; 22:ijms22041625. [PMID: 33562731 PMCID: PMC7915266 DOI: 10.3390/ijms22041625] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/30/2021] [Accepted: 01/31/2021] [Indexed: 12/26/2022] Open
Abstract
The distinct properties of allo-reactive T-cell repertoires are not well understood. To investigate whether auto-reactive and allo-reactive T-cell repertoires encoded distinct properties, we used dextramer enumeration, enrichment, single-cell T-cell receptor (TCR) sequencing and multiparameter analysis. We found auto-reactive and allo-reactive T-cells differed in mean ex vivo frequency which was antigen dependent. Allo-reactive T-cells showed clear differences in TCR architecture, with enriched usage of specific T-cell receptor variable (TRBJ) genes and broader use of T-cell receptor variable joining (TRBJ) genes. Auto-reactive T-cell repertoires exhibited complementary determining regions three (CDR3) lengths using a Gaussian distribution whereas allo-reactive T-cell repertoires exhibited distorted patterns in CDR3 length. CDR3 loops from allo-reactive T-cells showed distinct physical-chemical properties, tending to encode loops that were more acidic in charge. Allo-reactive T-cell repertoires differed in diversity metrics, tending to show increased overall diversity and increased homogeneity between repertoires. Motif analysis of CDR3 loops showed allo-reactive T-cell repertoires differed in motif preference which included broader motif use. Collectively, these data conclude that allo-reactive T-cell repertoires are indeed different to auto-reactive repertoires and provide tangible metrics for further investigations and validation. Given that the antigens studied here are overexpressed on multiple cancers and that allo-reactive TCRs often show increased ligand affinity, this new TCR bank also has translational potential for adoptive cell therapy, soluble TCR-based therapy and rational TCR design.
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46
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Holland CJ, Crean RM, Pentier JM, de Wet B, Lloyd A, Srikannathasan V, Lissin N, Lloyd KA, Blicher TH, Conroy PJ, Hock M, Pengelly RJ, Spinner TE, Cameron B, Potter EA, Jeyanthan A, Molloy PE, Sami M, Aleksic M, Liddy N, Robinson RA, Harper S, Lepore M, Pudney CR, van der Kamp MW, Rizkallah PJ, Jakobsen BK, Vuidepot A, Cole DK. Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA. J Clin Invest 2021; 130:2673-2688. [PMID: 32310221 DOI: 10.1172/jci130562] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 02/11/2020] [Indexed: 01/09/2023] Open
Abstract
Tumor-associated peptide-human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface-expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.
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Affiliation(s)
| | - Rory M Crean
- Department of Biology and Biochemistry and.,Doctoral Training Centre in Sustainable Chemical Technologies, University of Bath, Bath, United Kingdom
| | | | - Ben de Wet
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | | | | | - Katy A Lloyd
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | - Paul J Conroy
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | - Miriam Hock
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | | | - Brian Cameron
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | | | | | - Malkit Sami
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | - Milos Aleksic
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | | | | | - Marco Lepore
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom
| | | | | | - Pierre J Rizkallah
- Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
| | | | | | - David K Cole
- Immunocore Ltd., Milton Park, Abingdon, United Kingdom.,Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
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47
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Van De Vyver AJ, Weinzierl T, Eigenmann MJ, Frances N, Herter S, Buser RB, Somandin J, Diggelmann S, Limani F, Lehr T, Bacac M, Walz AC. Predicting Tumor Killing and T-Cell Activation by T-Cell Bispecific Antibodies as a Function of Target Expression: Combining In Vitro Experiments with Systems Modeling. Mol Cancer Ther 2020; 20:357-366. [PMID: 33298591 DOI: 10.1158/1535-7163.mct-20-0269] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/03/2020] [Accepted: 11/17/2020] [Indexed: 11/16/2022]
Abstract
Targeted T-cell redirection is a promising field in cancer immunotherapy. T-cell bispecific antibodies (TCB) are novel antibody constructs capable of binding simultaneously to T cells and tumor cells, allowing cross-linking and the formation of immunologic synapses. This in turn results in T-cell activation, expansion, and tumor killing. TCB activity depends on system-related properties such as tumor target antigen expression as well as antibody properties such as binding affinities to target and T cells. Here, we developed a systems model integrating in vitro data to elucidate further the mechanism of action and to quantify the cytotoxic effects as the relationship between targeted antigen expression and corresponding TCB activity. In the proposed model, we capture relevant processes, linking immune synapse formation to T-cell activation, expansion, and tumor killing for TCBs in vitro to differentiate the effect between tumor cells expressing high or low levels of the tumor antigen. We used cibisatamab, a TCB binding to carcinoembryonic antigen (CEA), to target different tumor cell lines with high and low CEA expression in vitro We developed a model to capture and predict our observations, as a learn-and-confirm cycle. Although full tumor killing and substantial T-cell activation was observed in high expressing tumor cells, the model correctly predicted partial tumor killing and minimal T-cell activation in low expressing tumor cells when exposed to cibisatamab. Furthermore, the model successfully predicted cytotoxicity across a wide range of tumor cell lines, spanning from very low to high CEA expression.
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Affiliation(s)
- Arthur J Van De Vyver
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland. .,Saarland University, Department of Clinical Pharmacy, Saarbrücken, Germany
| | - Tina Weinzierl
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Miro J Eigenmann
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland
| | - Nicolas Frances
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland
| | - Sylvia Herter
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Regula B Buser
- Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center, Zürich, Switzerland
| | - Jitka Somandin
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Sarah Diggelmann
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Florian Limani
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Thorsten Lehr
- Saarland University, Department of Clinical Pharmacy, Saarbrücken, Germany
| | - Marina Bacac
- Roche Pharma Research and Early Development, Cancer Immunotherapy Department 2, Roche Innovation Center, Zürich, Switzerland
| | - Antje-Christine Walz
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland
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Mor JM, Rokohl AC, Mauch C, Heindl LM. Interdisciplinary Surveillance of Ocular Melanomas: Experiences in a German Tertiary Centre. Klin Monbl Augenheilkd 2020; 238:85-91. [PMID: 33242884 DOI: 10.1055/a-1264-7962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND In contrast to cutaneous melanoma, there are no uniform guidelines regarding surveillance of ocular (uveal, conjunctival) melanomas. A consented standard operating procedure (SOP) by the "Netzwerk onkologische Spitzenzentren" Germany only exists for conjunctival melanoma but not for uveal melanoma. Surveillance is partially based on German S3-guidelines for cutaneous melanoma and is carried out by oncologic centres in a multidisciplinary approach. This study aims to evaluate patients' adherence to surveillance programs and whether surveillance recommendations (examinations, intervals) can be realised. METHODS Retrospective analysis of all ocular melanoma patients overseen at the University Hospital of Cologne between 2008 and 2019. The study evaluates rates of successful patient integration into a standardized surveillance program and patients' surveillance adherence, subject to age, gender, primary therapy and tumour entity, respectively. RESULTS 99 patients were included (56 female, 43 male), 83 of which had uveal melanomas and 16 conjunctival melanomas. Mean follow-up was 59 months. 81% of patients were integrated into a surveillance program. Surveillance was performed according to published recommendations in 78%. 13% of patients dropped out of the surveillance program after a mean period of 38 months. CONCLUSIONS Our data show a growing number of patients in standardized surveillance. However, there are still gaps. There is a need for guidelines specifically designed for ocular melanomas, allowing centres to offer patients an individualized approach.
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Affiliation(s)
- Joel M Mor
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Deutschland
| | - Alexander C Rokohl
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Deutschland
| | - Cornelia Mauch
- Klinik und Poliklinik für Dermatologie, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Deutschland
| | - Ludwig M Heindl
- Zentrum für Augenheilkunde, Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Deutschland
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Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, Gupta A, Vardeu A, Leach E, Naidoo R, Stanhope S, Lewis S, Hurst J, O'Kelly I, Sznol M. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin Cancer Res 2020; 26:5869-5878. [PMID: 32816891 PMCID: PMC9210997 DOI: 10.1158/1078-0432.ccr-20-1247] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/11/2020] [Accepted: 08/14/2020] [Indexed: 01/08/2023]
Abstract
PURPOSE Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. PATIENTS AND METHODS Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. RESULTS Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. CONCLUSIONS These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.
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Affiliation(s)
- Mark R Middleton
- Department of Oncology, Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom.
| | | | - Victoria K Woodcock
- Department of Oncology, Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom
| | - Pippa Corrie
- Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Neil M Steven
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Thomas R Jeffry Evans
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Alan Anthoney
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | | | - Omid Hamid
- Immunooncology, The Angeles Clinic and Research Institute, Los Angeles, California
| | - Avinash Gupta
- Department of Oncology, Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom
| | | | - Emma Leach
- Immunocore Ltd, Abingdon, Oxford, United Kingdom
| | | | | | - Sion Lewis
- Immunocore Ltd, Abingdon, Oxford, United Kingdom
| | - Jacob Hurst
- Immunocore Ltd, Abingdon, Oxford, United Kingdom
| | - Ita O'Kelly
- Immunocore Ltd, Abingdon, Oxford, United Kingdom
| | - Mario Sznol
- Yale Cancer Center, Yale School of Medicine, Yale, Connecticut
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50
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Li Y, Shi J, Yang J, Ge S, Zhang J, Jia R, Fan X. Uveal melanoma: progress in molecular biology and therapeutics. Ther Adv Med Oncol 2020; 12:1758835920965852. [PMID: 33149769 PMCID: PMC7586035 DOI: 10.1177/1758835920965852] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 09/16/2020] [Indexed: 12/15/2022] Open
Abstract
Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting: GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.
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Affiliation(s)
- Yongyun Li
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jiahao Shi
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jie Yang
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jianming Zhang
- National Research Center for Translational Medicine, Shanghai State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200001, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200001, China
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200001, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, 833 Zhizaoju Road, Huangpu District, Shanghai 200001, China
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