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1
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Bhutani B, Sharma V, Ganguly NK, Rana R. Unravelling the modified T cell receptor through Gen-Next CAR T cell therapy in Glioblastoma: Current status and future challenges. Biomed Pharmacother 2025; 186:117987. [PMID: 40117901 DOI: 10.1016/j.biopha.2025.117987] [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: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025] Open
Abstract
PURPOSE Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity. METHODS In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy. FINDINGS To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes. IMPLICATIONS CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.
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Affiliation(s)
- Bhavya Bhutani
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vyoma Sharma
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
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2
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Sterner RC, Sterner RM. EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma. Front Oncol 2024; 14:1434495. [PMID: 39364321 PMCID: PMC11446898 DOI: 10.3389/fonc.2024.1434495] [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: 05/17/2024] [Accepted: 09/03/2024] [Indexed: 10/05/2024] Open
Abstract
Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells.
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Affiliation(s)
- Robert C Sterner
- Department of Neurosurgery, Inova Fairfax Medical Campus, Fairfax, VA, United States
| | - Rosalie M Sterner
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
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3
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Bagley SJ, Binder ZA, Lamrani L, Marinari E, Desai AS, Nasrallah MP, Maloney E, Brem S, Lustig RA, Kurtz G, Alonso-Basanta M, Bonté PE, Goudot C, Richer W, Piaggio E, Kothari S, Guyonnet L, Guerin CL, Waterfall JJ, Mohan S, Hwang WT, Tang OY, Logun M, Bhattacharyya M, Markowitz K, Delman D, Marshall A, Wherry EJ, Amigorena S, Beatty GL, Brogdon JL, Hexner E, Migliorini D, Alanio C, O'Rourke DM. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. NATURE CANCER 2024; 5:517-531. [PMID: 38216766 DOI: 10.1038/s43018-023-00709-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 12/13/2023] [Indexed: 01/14/2024]
Abstract
We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.
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Affiliation(s)
- Stephen J Bagley
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
| | - Zev A Binder
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Lamia Lamrani
- Clinical Immunology Laboratory, Institut Curie, Paris, France
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Eliana Marinari
- Agora Cancer Research Center, Lausanne, Switzerland
- Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland
- Swiss Cancer Center Léman, Lausanne and Geneva, Geneva, Switzerland
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
| | - Arati S Desai
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - MacLean P Nasrallah
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Eileen Maloney
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Steven Brem
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Robert A Lustig
- Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Goldie Kurtz
- Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Michelle Alonso-Basanta
- Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Pierre-Emmanuel Bonté
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
| | - Christel Goudot
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
| | - Wilfrid Richer
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
- Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France
| | - Eliane Piaggio
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
| | - Shawn Kothari
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Lea Guyonnet
- Cytometry Platform, CurieCoreTech, Institut Curie, Paris, France
| | - Coralie L Guerin
- Cytometry Platform, CurieCoreTech, Institut Curie, Paris, France
| | - Joshua J Waterfall
- Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France
- INSERM U830, PSL University, Institut Curie Research Cente, Paris, France
| | - Suyash Mohan
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Oliver Y Tang
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Meghan Logun
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Meghna Bhattacharyya
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Kelly Markowitz
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Devora Delman
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Amy Marshall
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - E John Wherry
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health, Cambridge, MA, USA
| | - Sebastian Amigorena
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France
| | - Gregory L Beatty
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Elizabeth Hexner
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Denis Migliorini
- Agora Cancer Research Center, Lausanne, Switzerland
- Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland
- Swiss Cancer Center Léman, Lausanne and Geneva, Geneva, Switzerland
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
| | - Cecile Alanio
- Clinical Immunology Laboratory, Institut Curie, Paris, France.
- INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
| | - Donald M O'Rourke
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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4
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Ramapriyan R, Sun J, Curry A, Richardson LG, Ramesh T, Gaffey MA, Gedeon PC, Gerstner ER, Curry WT, Choi BD. The Role of Antibody-Based Therapies in Neuro-Oncology. Antibodies (Basel) 2023; 12:74. [PMID: 37987252 PMCID: PMC10660525 DOI: 10.3390/antib12040074] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/16/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
This review explores the evolving landscape of antibody-based therapies in neuro-oncology, in particular, immune checkpoint inhibitors and immunomodulatory antibodies. We discuss their mechanisms of action, blood-brain barrier (BBB) penetration, and experience in neuro-oncological conditions. Evidence from recent trials indicates that while these therapies can modulate the tumor immune microenvironment, their clinical benefits remain uncertain, largely due to challenges with BBB penetration and tumor-derived immunosuppression. This review also examines emerging targets such as TIGIT and LAG3, the potential of antibodies in modulating the myeloid compartment, and tumor-specific targets for monoclonal antibody therapy. We further delve into advanced strategies such as antibody-drug conjugates and bispecific T cell engagers. Lastly, we explore innovative techniques being investigated to enhance antibody delivery, including CAR T cell therapy. Despite current limitations, these therapies hold significant therapeutic potential for neuro-oncology. Future research should focus on optimizing antibody delivery to the CNS, identifying novel biological targets, and discovering combination therapies to address the hostile tumor microenvironment.
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Affiliation(s)
- Rishab Ramapriyan
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
| | - Jing Sun
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
| | - Annabel Curry
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
| | - Leland G. Richardson
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
| | - Tarun Ramesh
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
| | - Matthew A. Gaffey
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
| | - Patrick C. Gedeon
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Elizabeth R. Gerstner
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - William T. Curry
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
| | - Bryan D. Choi
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA (A.C.); (L.G.R.); (W.T.C.)
- Harvard Medical School, Boston, MA 02115, USA (E.R.G.)
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5
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Tang OY, Binder ZA, O'Rourke DM, Bagley SJ. Optimizing CAR-T Therapy for Glioblastoma. Mol Diagn Ther 2023; 27:643-660. [PMID: 37700186 DOI: 10.1007/s40291-023-00671-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2023] [Indexed: 09/14/2023]
Abstract
Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors. Glioblastoma is the most common primary malignant brain tumor in adults and remains a major unmet medical need. Attempts at harnessing the potential of chimeric antigen receptor T-cell therapy for glioblastoma have resulted in glimpses of promise but have been met with substantial challenges. In this focused review, we discuss current and future strategies being developed to optimize chimeric antigen receptor T cells for efficacy in patients with glioblastoma, including the identification and characterization of new target antigens, reversal of T-cell dysfunction with novel chimeric antigen receptor constructs, regulatable platforms, and gene knockout strategies, and the use of combination therapies to overcome the immune-hostile microenvironment.
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Affiliation(s)
- Oliver Y Tang
- Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA
| | - Zev A Binder
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Donald M O'Rourke
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Stephen J Bagley
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
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6
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Shahabifard H, Zarei M, Kookli K, Esmalian Afyouni N, Soltani N, Maghsoodi S, Adili A, Mahmoudi J, Shomali N, Sandoghchian Shotorbani S. An updated overview of the application of CAR-T cell therapy in neurological diseases. Biotechnol Prog 2023; 39:e3356. [PMID: 37198722 DOI: 10.1002/btpr.3356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/29/2023] [Accepted: 05/03/2023] [Indexed: 05/19/2023]
Abstract
Genetically modified immune cells, especially CAR-T cells, have captured the attention of scientists over the past 10 years. In the fight against cancer, these cells have a special place. Treatment for hematological cancers, autoimmune disorders, and cancers must include CAR-T cell therapy. Determining the therapeutic targets, side effects, and use of CAR-T cells in neurological disorders, including cancer and neurodegenerative diseases, is the goal of this study. Due to advancements in genetic engineering, CAR-T cells have become crucial in treating some neurological disorders. CAR-T cells have demonstrated a positive role in treating neurological cancers like Glioblastoma and Neuroblastoma due to their ability to cross the blood-brain barrier and use diverse targets. However, CAR-T cell therapy for MS diseases is being researched and could be a potential treatment option. This study aimed to access the most recent studies and scientific articles in the field of CAR-T cells in neurological diseases and/or disorders.
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Affiliation(s)
- Hesam Shahabifard
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Zarei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Keihan Kookli
- International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Nazgol Esmalian Afyouni
- Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Narges Soltani
- School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Sairan Maghsoodi
- Department of Laboratory Sciences, Faculty of Paramedical Sciences, Kurdistan University of Medical Sciences (MUK), Sanandaj, Iran
| | - Ali Adili
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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7
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Olivet MM, Brown MC, Reitman ZJ, Ashley DM, Grant GA, Yang Y, Markert JM. Clinical Applications of Immunotherapy for Recurrent Glioblastoma in Adults. Cancers (Basel) 2023; 15:3901. [PMID: 37568717 PMCID: PMC10416859 DOI: 10.3390/cancers15153901] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite standard therapies, including resection and chemoradiation, recurrence is virtually inevitable. Current treatment for recurrent glioblastoma (rGBM) is rapidly evolving, and emerging therapies aimed at targeting primary GBM are often first tested in rGBM to demonstrate safety and feasibility, which, in recent years, has primarily been in the form of immunotherapy. The purpose of this review is to highlight progress in clinical trials of immunotherapy for rGBM, including immune checkpoint blockade, oncolytic virotherapy, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccine and immunotoxins. Three independent reviewers covered literature, published between the years 2000 and 2022, in various online databases. In general, the efficacy of immunotherapy in rGBM remains uncertain, and is limited to subsets/small cohorts of patients, despite demonstrating feasibility in early-stage clinical trials. However, considerable progress has been made in understanding the mechanisms that may preclude rGBM patients from responding to immunotherapy, as well as in developing new approaches/combination strategies that may inspire optimism for the utility of immunotherapy in this devastating disease. Continued trials are necessary to further assess the best therapeutic avenues and ascertain which treatments might benefit each patient individually.
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Affiliation(s)
- Meagan Mandabach Olivet
- Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - Michael C. Brown
- Department of Neurosurgery, Duke University, Durham, NC 27710, USA; (M.C.B.); (D.M.A.); (G.A.G.)
| | - Zachary J. Reitman
- Department of Radiation Oncology, Duke University, Durham, NC 27710, USA;
| | - David M. Ashley
- Department of Neurosurgery, Duke University, Durham, NC 27710, USA; (M.C.B.); (D.M.A.); (G.A.G.)
| | - Gerald A. Grant
- Department of Neurosurgery, Duke University, Durham, NC 27710, USA; (M.C.B.); (D.M.A.); (G.A.G.)
| | - Yuanfan Yang
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - James M. Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
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8
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Rocha Pinheiro SL, Lemos FFB, Marques HS, Silva Luz M, de Oliveira Silva LG, Faria Souza Mendes dos Santos C, da Costa Evangelista K, Calmon MS, Sande Loureiro M, Freire de Melo F. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol 2023; 14:138-159. [PMID: 37124134 PMCID: PMC10134201 DOI: 10.5306/wjco.v14.i4.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023] Open
Abstract
Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.
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Affiliation(s)
- Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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9
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Abbasi S, Totmaj MA, Abbasi M, Hajazimian S, Goleij P, Behroozi J, Shademan B, Isazadeh A, Baradaran B. Chimeric antigen receptor T (CAR-T) cells: Novel cell therapy for hematological malignancies. Cancer Med 2023; 12:7844-7858. [PMID: 36583504 PMCID: PMC10134288 DOI: 10.1002/cam4.5551] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 07/23/2022] [Accepted: 12/03/2022] [Indexed: 12/31/2022] Open
Abstract
Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR-T), which includes the engineering of T cells to recognize tumor-specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR-T-cell-based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non-Hodgkin's lymphoma (NHL). However, CAR-T-cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR-T-cell-based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR-T-cell therapy.
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Affiliation(s)
- Samane Abbasi
- Department of Biology, Faculty of SciencesUniversity of GuilanRashtIran
| | - Milad Asghari Totmaj
- Department of Clinical Immunology, Faculty of MedicineThe University of ManchesterManchesterUK
| | - Masoumeh Abbasi
- Department of Microbiology, Malekan BranchIslamic Azad UniversityMalekanIran
| | - Saba Hajazimian
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Pouya Goleij
- Department of Genetics, Faculty of BiologySana Institute of Higher EducationSariIran
| | - Javad Behroozi
- Department of Genetics and Biotechnology, School of MedicineAJA University of Medical SciencesTehranIran
| | - Behrouz Shademan
- Department of Medical Biology, Faculty of MedicineEge UniversityIzmirTurkey
| | - Alireza Isazadeh
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
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10
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Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nat Rev Clin Oncol 2023; 20:49-62. [PMID: 36418477 DOI: 10.1038/s41571-022-00704-3] [Citation(s) in RCA: 199] [Impact Index Per Article: 99.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 11/25/2022]
Abstract
Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cell-mediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR T cell clinical trials involving patients with solid tumours, highlighting the importance of establishing strategies to predict, mitigate and control the onset of this effect. In this Review, we summarize current clinical evidence of OTOT with CAR T cells in the treatment of solid tumours and discuss the utility of preclinical mouse models in predicting clinical OTOT. We then describe novel strategies being developed to improve the specificity of CAR T cells in solid tumours, particularly the role of affinity tuning of target binders, logic circuits and synthetic biology. Furthermore, we highlight control strategies that can be used to mitigate clinical OTOT following cell infusion such as regulating or eliminating CAR T cell activity, exogenous control of CAR expression, and local administration of CAR T cells.
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11
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Zhang J, Siller-Farfán JA. Current and future perspectives of chimeric antigen receptors against glioblastoma. IMMUNOTHERAPY ADVANCES 2022; 2:ltac014. [PMID: 36284838 PMCID: PMC9585667 DOI: 10.1093/immadv/ltac014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/27/2022] [Indexed: 11/14/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant form of cancer in the central nervous system; even with treatment, it has a 5-year survival rate of 7.2%. The adoptive cell transfer (ACT) of T cells expressing chimeric antigen receptors (CARs) has shown a remarkable success against hematological malignancies, namely leukemia and multiple myeloma. However, CAR T cell therapy against solid tumors, and more specifically GBM, is still riddled with challenges preventing its widespread adoption. Here, we first establish the obstacles in ACT against GBM, including on-target/off-tumor toxicity, antigen modulation, tumor heterogeneity, and the immunosuppressive tumor microenvironment. We then present recent preclinical and clinical studies targeting well-characterized GBM antigens, which include the interleukin-13 receptor α2 and the epidermal growth factor receptor. Afterward, we turn our attention to alternative targets in GBM, including less-explored antigens such as B7-H3 (CD276), carbonic anhydrase IX, and the GD2 ganglioside. We also discuss additional target ligands, namely CD70, and natural killer group 2 member D ligands. Finally, we present the possibilities afforded by novel CAR architectures. In particular, we examine the use of armored CARs to improve the survival and proliferation of CAR T cells. We conclude by discussing the advantages of tandem and synNotch CARs when targeting multiple GBM antigens.
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Affiliation(s)
- Josephine Zhang
- Department of Biology, Johns Hopkins University, 3400 N Charles St , Baltimore 21218, United States
- St Anne’s College, University of Oxford, Woodstock Rd , Oxford OX2 6HS, United Kingdom
| | - Jesús A Siller-Farfán
- Sir William Dunn School of Pathology, University of Oxford, S Parks Rd , Oxford OX1 3DP, United Kingdom
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12
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Karimi-Shahri M, Khorramdel M, Zarei S, Attarian F, Hashemian P, Javid H. Glioblastoma, an opportunity T cell trafficking could bring for the treatment. Mol Biol Rep 2022; 49:9863-9875. [DOI: 10.1007/s11033-022-07510-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/22/2022] [Indexed: 01/22/2023]
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13
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Tang OY, Tian L, Yoder T, Xu R, Kulikovskaya I, Gupta M, Melenhorst JJ, Lacey SF, O’Rourke DM, Binder ZA. PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response. Front Immunol 2022; 13:872756. [PMID: 35603165 PMCID: PMC9120664 DOI: 10.3389/fimmu.2022.872756] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/12/2022] [Indexed: 12/11/2022] Open
Abstract
The epidermal growth factor receptor variant III (EGFRvIII) has been investigated as a therapeutic target for chimeric antigen receptor (CAR) T cell therapy in glioblastoma. Earlier research demonstrated that phenotypic and genotypic characteristics in T cells and CAR T product predicted therapeutic success in hematologic malignancies, to date no determinants for clinical response in solid tumors have been identified. We analyzed apheresis and infusion products from the first-in-human trial of EGFRvIII-directed CAR T for recurrent glioblastoma (NCT02209376) by flow cytometry. Clinical response was quantified via engraftment in peripheral circulation and progression-free survival (PFS), as determined by the time from CAR T infusion to first radiographic evidence of progression. The CD4+CAR T cell population in patient infusion products demonstrated PD1 expression which positively correlated with AUC engraftment and PFS. On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with engraftment or PFS. The frequencies of PD1+GZMB+ and PD1+HLA-DR+ CAR T cells in the CD4+ infusion products were directly proportional to AUC and PFS. No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.
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Affiliation(s)
- Oliver Y. Tang
- GBM Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Lifeng Tian
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Todd Yoder
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Rong Xu
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Irina Kulikovskaya
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Minnal Gupta
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jan Joseph Melenhorst
- GBM Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Simon F. Lacey
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Donald M. O’Rourke
- GBM Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Zev A. Binder
- GBM Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Zev A. Binder,
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14
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Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Front Immunol 2022; 13:817296. [PMID: 35265074 PMCID: PMC8899093 DOI: 10.3389/fimmu.2022.817296] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/20/2022] [Indexed: 12/15/2022] Open
Abstract
Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.
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Affiliation(s)
- Ya-Jui Lin
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States.,Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Leila A Mashouf
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States.,Harvard Medical School, Boston, MA, United States
| | - Michael Lim
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States
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15
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Zeng W, Zhang P. Resistance and recurrence of malignancies after CAR-T cell therapy. Exp Cell Res 2022; 410:112971. [PMID: 34906583 DOI: 10.1016/j.yexcr.2021.112971] [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: 09/24/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 11/04/2022]
Abstract
The emergence of chimeric antigen receptor T (CAR-T) cell therapy has ushered a new era in cancer therapy, especially the treatment of hematological malignancies. However, resistance and recurrence still occur in some patients after CAR-T cell treatment. CAR-T cell inefficiency and tumor escape have emerged as the main challenges for the long-term disease control of B cell malignancies by this promising immunotherapy. In solid tumor treatment, CAR-T cells must also overcome many hurdles from the tumor or immune-suppressed tumor environment, which have become obstacles to the advancement of CAR-T therapy. Therefore, an understanding of the mechanisms underlying post-CAR treatment failure in patients is necessary. In this review, we characterize some mechanisms of resistance and recurrence after CAR-T cell therapy and correspondingly suggest reasonable treatment strategies.
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Affiliation(s)
- Wanying Zeng
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Pumin Zhang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, 310003, China; Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang Province, 310058, China.
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16
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Pineal parenchymal tumor of intermediate differentiation: a systematic review and contemporary management of 389 cases reported during the last two decades. Neurosurg Rev 2021; 45:1135-1155. [PMID: 34668090 DOI: 10.1007/s10143-021-01674-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/21/2021] [Accepted: 10/07/2021] [Indexed: 12/29/2022]
Abstract
Pineal parenchymal tumor of intermediate differentiation (PPTID) is a WHO grade II and III tumor arising from pineal parenchymal cells. PPTID is a rare tumor accounting for less than 1% of all primary central nervous system neoplasms. Therefore, reports describing the clinical characteristics and biological features of PPTID are lacking. Moreover, the therapeutic strategy remains controversial. The current study aimed to evaluate treatment results and problems of contemporary therapeutic modalities of PPTID based on its features compared with other pineal parenchymal tumors. A comprehensive systematic literature review of 69 articles was performed, including articles on PPTID (389 patients) and similar tumors. Patient demographics, disease presentation, imaging characteristics, biological features, and current therapeutic options and their results were reviewed. We found that histopathological findings based on current WHO classification are well associated with survival; however, identifying and treating aggressive PPTID cases with uncommon features could be problematic. A molecular and genetic approach may help improve diagnostic accuracy. Therapeutic strategy, especially for grade III and aforementioned uncommon and aggressive tumors, remains controversial. A combination therapy involving maximum tumor resection, chemotherapy, and radiotherapy could be the first line of treatment. However, although challenging, a large prospective study would be required to identify ways to improve the clinical results of PPTID treatment.
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17
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Zeng XX, Zeng J, Zhu B. Future generation of combined multimodal approach to treat brain glioblastoma multiforme and potential impact on micturition control. Rev Neurosci 2021; 33:313-326. [PMID: 34529907 DOI: 10.1515/revneuro-2021-0068] [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: 05/16/2021] [Accepted: 08/26/2021] [Indexed: 11/15/2022]
Abstract
Glioblastoma remains lethal even when treated with standard therapy. This review aims to outline the recent development of various advanced therapeutics for glioblastoma and briefly discuss the potential impact of glioblastoma and some of its therapeutic approaches on the neurological function micturition control. Although immunotherapy led to success in treating hematological malignancies, but no similar success occurred in treatment for brain glioblastoma. Neither regenerative medicine nor stem cell therapy led to astounding success in glioblastoma. However, CRISPR Cas system holds potential in multiple applications due to its capacity to knock-in and knock-out genes, modify immune cells and cell receptors, which will enable it to address clinical challenges in immunotherapy such as CAR-T and regenerative therapy for brain glioblastoma, improving the precision and safety of these approaches. The studies mentioned in this review could indicate that glioblastoma is a malignant disease with multiple sophisticated barriers to be overcome and more challenges might arise in the attempt of researchers to yield a successful cure. A multimodal approach of future generation of refined and safe therapeutics derived from CRISPR Cas therapeutics, immunotherapy, and regenerative therapeutics mentioned in this review might prolong survival or even contribute towards a potential cure for glioblastoma.
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Affiliation(s)
- Xiao Xue Zeng
- Guangzhou United Family Hospital, Fangyuan Road 28, Haizhu District, Guangzhou, Postcode: 510000, Guangdong Province, P. R. China
| | - Jianwen Zeng
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Yinquan Road B24, Qingyuan City, Postcode: 511500, Guangdong Province, P. R. China
| | - Baoyi Zhu
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Yinquan Road B24, Qingyuan City, Postcode: 511500, Guangdong Province, P. R. China
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18
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Zheng Y, Nandakumar KS, Cheng K. Optimization of CAR-T Cell-Based Therapies Using Small-Molecule-Based Safety Switches. J Med Chem 2021; 64:9577-9591. [PMID: 34191515 DOI: 10.1021/acs.jmedchem.0c02054] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chimeric antigen receptor T cell therapy has demonstrated antileukemia efficacy. However, this therapeutic approach is hampered by severe cytokine release syndrome, which is a major impediment to its widespread application in the clinic. The safety of this approach can be improved by engineering a rapid and reversible "off" or "on" safety switch for CAR-T cells. Cutting-edge investigations combining the advantages of genetic engineering and chemical technology have led to the invention of small-molecule-based safety switches for CAR-T cells. Small molecules such as FITC, folate, rimiducid, rapamycin, proteolysis-targeting chimera (PROTAC) compounds, and dasatinib are being investigated to design such safety switches. Optimized CAR-T cells may have enhanced therapeutic efficiency with fewer adverse effects. Herein we summarize and classify current novel small-molecule-based safety switches for CAR-T cells that aim to provide pharmacological control over the activities and toxicities associated with CAR-T cell-based cancer immunotherapies.
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Affiliation(s)
- Yanjun Zheng
- Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kutty Selva Nandakumar
- Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kui Cheng
- Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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19
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Abstract
Chimeric antigen receptor T (CAR-T) cells, an immunotherapy that demonstrates marked success in treatment of hematologic malignancies, are an emergent therapeutic for patients with glioblastoma (GBM). GBM CAR-T trials have focused on targeting well-characterized antigens in the pathogenesis of GBM. Early stage trials demonstrate initial success in terms of safety and tolerability. There is preliminary evidence of antitumor activity and localization of the CAR-T product to tumoral sites. There are mixed results regarding patient outcomes. Ongoing GBM CAR-T trials will target novel antigens, explore CAR-T combination therapy, design multivalent CAR constructs, and assess the impact of lymphodepletion before CAR-T delivery.
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Affiliation(s)
- Thilan Tudor
- University of Pennsylvania, 3600 Hamilton Walk, Stemmler Hall, Room 176, Philadelphia, PA 19104
| | - Zev A Binder
- University of Pennsylvania, 3600 Hamilton Walk, Stemmler Hall, Room 176, Philadelphia, PA 19104.
| | - Donald M O'Rourke
- John Templeton, Jr. M.D. Professor in Neurosurgery, Hospital of the University of Pennsylvania, 3400 Spruce St. Philadelphia, PA 19104, USA. https://twitter.com/DrORourke2
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Abstract
PURPOSE OF REVIEW This review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system-specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction. RECENT FINDINGS The success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.
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Affiliation(s)
- Abigail L. Mende
- Department of Neurological Surgery, University of California, Diller Family Cancer Research Building HD 472, Box 520, 1450 3rd Street San Francisco, Helen, CA 94158 USA
| | - Jessica D. Schulte
- Department of Neurological Surgery, University of California, Diller Family Cancer Research Building HD 472, Box 520, 1450 3rd Street San Francisco, Helen, CA 94158 USA
- Department of Neurology, University of California, San Francisco, CA USA
| | - Hideho Okada
- Department of Neurological Surgery, University of California, Diller Family Cancer Research Building HD 472, Box 520, 1450 3rd Street San Francisco, Helen, CA 94158 USA
- The Parker Institute for Cancer Immunotherapy, Diller Family Cancer Research Building HD 472, Box 520, 1450 3rd Street San Francisco, Helen, CA 94158 USA
- Cancer Immunotherapy Program, University of California, San Francisco, CA USA
| | - Jennifer L. Clarke
- Department of Neurological Surgery, University of California, Diller Family Cancer Research Building HD 472, Box 520, 1450 3rd Street San Francisco, Helen, CA 94158 USA
- Department of Neurology, University of California, San Francisco, CA USA
- Department of Clinical Neurology and Neurological Surgery, University of California San Francisco, Box 0372, 400 Parnassus Avenue, A895F, San Francisco, CA 94143-0372 USA
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21
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Guo F, Cui J. CAR-T in solid tumors: Blazing a new trail through the brambles. Life Sci 2020; 260:118300. [DOI: 10.1016/j.lfs.2020.118300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/31/2020] [Accepted: 08/13/2020] [Indexed: 02/07/2023]
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Nery de Albuquerque Rego G, da Hora Alves A, Penteado Nucci M, Bustamante Mamani J, Anselmo de Oliveira F, Gamarra LF. Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations. Int J Mol Sci 2020; 21:ijms21124490. [PMID: 32599834 PMCID: PMC7349965 DOI: 10.3390/ijms21124490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/12/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive tumor type whose resistance to conventional treatment is mediated, in part, by the angiogenic process. New treatments involving the application of nanoformulations composed of encapsulated drugs coupled to peptide motifs that direct drugs to specific targets triggered in angiogenesis have been developed to reach and modulate different phases of this process. We performed a systematic review with the search criterion (Glioblastoma OR Glioma) AND (Therapy OR Therapeutic) AND (Nanoparticle) AND (Antiangiogenic OR Angiogenesis OR Anti-angiogenic) in Pubmed, Scopus, and Cochrane databases, in which 312 articles were identified; of these, only 27 articles were included after selection and analysis of eligibility according to the inclusion and exclusion criteria. The data of the articles were analyzed in five contexts: the characteristics of the tumor cells; the animal models used to induce GBM for antiangiogenic treatment; the composition of nanoformulations and their physical and chemical characteristics; the therapeutic anti-angiogenic process; and methods for assessing the effects on antiangiogenic markers caused by therapies. The articles included in the review were heterogeneous and varied in practically all aspects related to nanoformulations and models. However, there was slight variance in the antiangiogenic effect analysis. CD31 was extensively used as a marker, which does not provide a view of the effects on the most diverse aspects involved in angiogenesis. Therefore, the present review highlighted the need for standardization between the different approaches of antiangiogenic therapy for the GBM model that allows a more effective meta-analysis and that helps in future translational studies.
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Affiliation(s)
| | - Arielly da Hora Alves
- Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil; (G.N.d.A.R.); (A.d.H.A.); (J.B.M.); (F.A.d.O.)
| | - Mariana Penteado Nucci
- LIM44-Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-903, Brazil;
| | - Javier Bustamante Mamani
- Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil; (G.N.d.A.R.); (A.d.H.A.); (J.B.M.); (F.A.d.O.)
| | | | - Lionel Fernel Gamarra
- Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil; (G.N.d.A.R.); (A.d.H.A.); (J.B.M.); (F.A.d.O.)
- Correspondence: ; Tel.: +55-11-2151-0243
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23
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Nakazawa T, Natsume A, Nishimura F, Morimoto T, Matsuda R, Nakamura M, Yamada S, Nakagawa I, Motoyama Y, Park YS, Tsujimura T, Wakabayashi T, Nakase H. Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on In Vitro Human Glioblastoma Cell Growth. Cells 2020; 9:cells9040998. [PMID: 32316275 PMCID: PMC7227242 DOI: 10.3390/cells9040998] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/09/2020] [Accepted: 04/15/2020] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma (GBM), which is the most common malignant brain tumor, is resistant to standard treatments. Immunotherapy might be a promising alternative for the treatment of this cancer. Chimeric antigen receptor (CAR) is an artificially modified fusion protein that can be engineered to direct the specificity and function of T cells against tumor antigens. However, the antitumor effects of EGFRvIII-targeting CAR-T (EvCAR-T) cells in GBM are limited. The inhibitory effect is induced by the interaction between programmed cell death protein 1 (PD-1) on activated EvCAR-T cells and its ligands on GBM cells. In the present study, PD-1-disrupted EvCAR-T cells were established using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The sgRNA/Cas9 expression vectors designed precisely disrupted the target region of PD-1 and inhibited the expression of PD-1 in EvCAR-T cells. The PD-1-disrupted EvCAR-T cells had an in vitro growth inhibitory effect on EGFRvIII-expressing GBM cells without altering the T-cell phenotype and the expression of other checkpoint receptors. In the future, the in vivo antitumor effect of this vector should be evaluated in order to determine if it could be applied clinically for improving the efficacy of EvCAR-T cell-based adoptive immunotherapy for GBM.
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Affiliation(s)
- Tsutomu Nakazawa
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
- Grandsoul Research Institute for Immunology, Inc., Uda 633-2221, Japan
- Correspondence: ; Tel.: +81-744-22-3051
| | - Atsushi Natsume
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Japan; (A.N.); (T.W.)
| | - Fumihiko Nishimura
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Takayuki Morimoto
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Ryosuke Matsuda
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Mitsutoshi Nakamura
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
- Clinic Grandsoul Nara, Uda 633-2221, Japan;
| | - Shuichi Yamada
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Ichiro Nakagawa
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Yasushi Motoyama
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | - Young-Soo Park
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
| | | | - Toshihiko Wakabayashi
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Japan; (A.N.); (T.W.)
| | - Hiroyuki Nakase
- Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan; (F.N.); (T.M.); (R.M.); (M.N.); (S.Y.); (I.N.); (Y.M.); (Y.-S.P.); (H.N.)
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24
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Wang Z, Cao YJ. Adoptive Cell Therapy Targeting Neoantigens: A Frontier for Cancer Research. Front Immunol 2020; 11:176. [PMID: 32194541 PMCID: PMC7066210 DOI: 10.3389/fimmu.2020.00176] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/23/2020] [Indexed: 12/19/2022] Open
Abstract
Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR), and ACT has made a great difference in treating multiple types of tumors. ACT is not perfect, and it can be followed by severe side effects, which hampers the application of ACT in clinical trials. One of the most promising methods to minimize side effects is to endow adoptive T cells with the ability to target neoantigens, which are specific to tumor cells. With the development of antigen screening technologies, more methods can be applied to discover neoantigens in cancer cells, such as whole-exome sequencing combined with mass spectrometry, neoantigen screening through an inventory-shared neoantigen peptide library, and neoantigen discovery via trogocytosis. In this review, we focus on the side effects of existing antigens and their solutions, illustrate the strategies of finding neoantigens in CAR-T and TCR-T therapies through methods reported by other researchers, and summarize the clinical behavior of these neoantigens.
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Affiliation(s)
- Zhidong Wang
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Yu J Cao
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
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25
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Titov A, Valiullina A, Zmievskaya E, Zaikova E, Petukhov A, Miftakhova R, Bulatov E, Rizvanov A. Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment. Cancers (Basel) 2020; 12:cancers12010125. [PMID: 31947775 PMCID: PMC7016531 DOI: 10.3390/cancers12010125] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/28/2019] [Accepted: 12/30/2019] [Indexed: 12/11/2022] Open
Abstract
Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.
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Affiliation(s)
- Aleksei Titov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
- Laboratory of Transplantation Immunology, National Hematology Research Centre, 125167 Moscow, Russia
| | - Aygul Valiullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
| | - Ekaterina Zmievskaya
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
| | - Ekaterina Zaikova
- Institute of Hematology, Almazov National Medical Research Center, 197341 Saint Petersburg, Russia;
| | - Alexey Petukhov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
- Institute of Hematology, Almazov National Medical Research Center, 197341 Saint Petersburg, Russia;
| | - Regina Miftakhova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
| | - Emil Bulatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
- Correspondence: (E.B.); (A.R.)
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.T.); (A.V.); (E.Z.); (A.P.); (R.M.)
- Correspondence: (E.B.); (A.R.)
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26
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Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions. Pharmacol Ther 2020; 205:107419. [DOI: 10.1016/j.pharmthera.2019.107419] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
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27
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Saxena D, Sheikh S, Kao G, Binder ZA, Alonso-Basanta M, O'Rourke DM, Nasrallah MP, Dorsey JF. Rapid and ultrasensitive digital PCR (dPCR) profiling of EGFRvIII in tumor cells and tissues. Neurooncol Adv 2019; 1:vdz030. [PMID: 31807732 PMCID: PMC6881905 DOI: 10.1093/noajnl/vdz030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Amplification of the epidermal growth factor receptor (EGFR) gene is commonly found in glioblastoma (GBM). About 57% GBM overexpresses EGFR and are associated with tumor progression, poor prognosis, and shorter life expectancy. Molecular profiling of solid tumors usually takes several weeks and may be biased by intrinsic tumor heterogeneity. Methods The unique sequence created by the fusion of exon 1 and exon 8 in EGFRvIII was used to guide the design of primers and a Minor Groove Binder (MGB) probe. Extracted total RNA was reverse transcribed and pre-amplified by PCR, followed by detection of the EGFRvIII mutation by dPCR. Results The lowest limit of quantification of our EGFRvIII assay was 0.003%. The EGFRvIII variant was identified in patient-derived glioma neurosphere cell lines, xenograft mouse model, and patient-derived tumor specimens. The overall workflow can be accomplished within 24 hours. In certain samples, EGFRvIII was detected when next-generation sequencing was unable to identify the variant. This finding highlights the ability of the dPCR assay to identify EGFRvIII mutations in heterogeneous solid tumors such as GBM in a rapid fashion by profiling samples from spatially distinct areas of tumors from the same patient. Conclusions In this study, we developed a highly sensitive digital PCR (dPCR) platform and leveraged our assay to detect the variant III alteration of EGFR (EGFRvIII) and amplified EGFR in patient-derived glioma neurosphere cell lines, orthotopic xenograft GBM mouse models, and patient-derived tumor specimens in less than 24 hours from minute quantities of starting material.
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Affiliation(s)
- Deeksha Saxena
- Department of Radiation Oncology.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Abramson Cancer Center Glioblastoma Translational Center of Excellence, Penn Medicine, Philadelphia, PA
| | | | - Gary Kao
- Department of Radiation Oncology
| | - Zev A Binder
- Department of Neurosurgery.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Abramson Cancer Center Glioblastoma Translational Center of Excellence, Penn Medicine, Philadelphia, PA
| | | | - Donald M O'Rourke
- Department of Neurosurgery.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Abramson Cancer Center Glioblastoma Translational Center of Excellence, Penn Medicine, Philadelphia, PA
| | - MacLean P Nasrallah
- Department of Pathology and Laboratory Medicine, Division of Neuropathology.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Abramson Cancer Center Glioblastoma Translational Center of Excellence, Penn Medicine, Philadelphia, PA
| | - Jay F Dorsey
- Department of Radiation Oncology.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Abramson Cancer Center Glioblastoma Translational Center of Excellence, Penn Medicine, Philadelphia, PA
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28
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Pan D, Zhou D, Cai W, Wu W, Tan WL, Zhou C, Lou Y. Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma. BMC Immunol 2019; 20:43. [PMID: 31722672 PMCID: PMC6854806 DOI: 10.1186/s12865-019-0320-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 09/23/2019] [Indexed: 11/10/2022] Open
Abstract
Background Mutant peptides presented by cancer cells are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EGFR (Epidermal Growth Factor Receptor) peptides have been tested as cancer vaccines in pancreatic, colorectal, and lung cancers. The immunogenicity of EGFR Del19 mutations, frequent in Chinese lung adenocarcinoma patients, remains unclear. Results We predicted the HLA binding epitopes of Del19 mutations of EGFR in Chinese lung adenocarcinoma patients with NetMHC software. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the EGFR-reactive IgG in lung cancer patients. Del19 mutations may be presented by multiple HLA Class I molecules, with delE746_A750 presented by 37.5% of Chinese population. For HLA Class II molecules, Del19 mutations of EGFR may be presented by multiple HLA-DRB1 molecules, with delE746_A750 presented by 58.1% of Chinese population. Serum reactivity to wild type EGFR protein was significantly higher in patients with Del19 EGFR mutations than those with EGFR L858R point mutation or with EGFR wild type genotype. Conclusions These findings suggest that Del19 mutations of EGFR, with an estimated frequency of 40% in Chinese lung adenocarcinoma patients, may serve as unique targets for immunotherapy in Chinese lung cancer patients.
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Affiliation(s)
- Deng Pan
- Shanghai Pudong New Area Mental Health Center affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Dapeng Zhou
- Shanghai Pudong New Area Mental Health Center affiliated with Tongji University School of Medicine, Shanghai, 200092, China. .,Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China.
| | - Weijing Cai
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Weibo Wu
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Wen Ling Tan
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Caicun Zhou
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Yanyan Lou
- Mayo Clinic, Jacksonville, FL, 32224, USA.
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29
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Bagley SJ, Desai AS, Linette GP, June CH, O'Rourke DM. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro Oncol 2019; 20:1429-1438. [PMID: 29509936 DOI: 10.1093/neuonc/noy032] [Citation(s) in RCA: 209] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.
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Affiliation(s)
- Stephen J Bagley
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Arati S Desai
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gerald P Linette
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carl H June
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Donald M O'Rourke
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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30
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Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, Ye Z, Qian Q. Current Progress in CAR-T Cell Therapy for Solid Tumors. Int J Biol Sci 2019; 15:2548-2560. [PMID: 31754328 PMCID: PMC6854376 DOI: 10.7150/ijbs.34213] [Citation(s) in RCA: 313] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 07/16/2019] [Indexed: 12/22/2022] Open
Abstract
Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) approved by US FDA (US Food and Drug Administration) are now used for treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) respectively in the US. Despite the progresses made in treating hematological malignancies, challenges still remain for use of CAR-T cell therapy to treat solid tumors. In this landscape, most studies have primarily focused on improving CAR-T cells and overcoming the unfavorable effects of tumor microenvironment on solid tumors. To further understand the current status and trend for developing CAR-T cell based therapies for various solid tumors, this review emphasizes on CAR-T techniques, current obstacles, and strategies for application, as well as necessary companion diagnostics for treatment of solid tumors with CAR-T cells.
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Affiliation(s)
- Shuo Ma
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Xinchun Li
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Xinyue Wang
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Liang Cheng
- Shanghai Baize Medical Laboratory, Shanghai, China.,Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Zhong Li
- Shanghai Baize Medical Laboratory, Shanghai, China
| | | | - Zhenlong Ye
- Shanghai Baize Medical Laboratory, Shanghai, China.,Shanghai Cell Therapy Research Institute, Shanghai, China.,Shanghai Engineering Research Center for Cell Therapy, Shanghai, China
| | - Qijun Qian
- Shanghai Baize Medical Laboratory, Shanghai, China.,Shanghai Cell Therapy Research Institute, Shanghai, China.,Shanghai Engineering Research Center for Cell Therapy, Shanghai, China
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31
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Cai W, Zhou D, Wu W, Tan WL, Wang J, Zhou C, Lou Y. MHC class II restricted neoantigen peptides predicted by clonal mutation analysis in lung adenocarcinoma patients: implications on prognostic immunological biomarker and vaccine design. BMC Genomics 2018; 19:582. [PMID: 30075702 PMCID: PMC6090856 DOI: 10.1186/s12864-018-4958-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 07/24/2018] [Indexed: 12/16/2022] Open
Abstract
Background Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. Results In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules. We found 18,175 expressed clonal somatic mutations, with an average of 124 per patient. The presentation of mutant peptides by an HLA(human leukocyte antigen) Class II molecule, HLA DRB1, were predicted by NetMHCIIpan3.1. 8804 neo-peptides, including 375 strong binders and 8429 weak binders were found. For HLA DRB1*01:01, 54 strong binders and 896 weak binders were found. The most commonly mutated genes with predicted neo-antigens are KRAS, TTN, RYR2, MUC16, TP53, USH2A, ZFHX4, KEAP1, STK11, FAT3, NAV3 and EGFR. Conclusions Our results support the feasibility of discovering individualized HLA Class II presented mutant peptides as candidates for immunodiagnosis and immunotherapy of lung adenocarcinoma. Electronic supplementary material The online version of this article (10.1186/s12864-018-4958-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Weijing Cai
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Dapeng Zhou
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China.
| | - Weibo Wu
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Wen Ling Tan
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Jiaqian Wang
- YuceBio Technology Co., Ltd, Shanghai, 201203, China
| | - Caicun Zhou
- Shanghai Pulmonary Hospital affiliated with Tongji University School of Medicine, Shanghai, 200092, China
| | - Yanyan Lou
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, 32224, USA.
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32
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O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2018; 9:9/399/eaaa0984. [PMID: 28724573 DOI: 10.1126/scitranslmed.aaa0984] [Citation(s) in RCA: 1171] [Impact Index Per Article: 167.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 05/09/2017] [Indexed: 12/18/2022]
Abstract
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.
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Affiliation(s)
- Donald M O'Rourke
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - MacLean P Nasrallah
- Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Arati Desai
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jan J Melenhorst
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Keith Mansfield
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Jennifer J D Morrissette
- Division of Precision and Computational Diagnostics, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maria Martinez-Lage
- Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Steven Brem
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eileen Maloney
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Angela Shen
- Novartis Oncology, East Hanover, NJ 07936, USA
| | - Randi Isaacs
- Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
| | - Suyash Mohan
- Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Simon F Lacey
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jean-Marc Navenot
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Zhaohui Zheng
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bruce L Levine
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hideho Okada
- Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA 02129, USA.
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Xia AL, Wang XC, Lu YJ, Lu XJ, Sun B. Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. Oncotarget 2017; 8:90521-90531. [PMID: 29163850 PMCID: PMC5685771 DOI: 10.18632/oncotarget.19361] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/18/2017] [Indexed: 12/11/2022] Open
Abstract
Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possibl e solutions and future perspectives.
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Affiliation(s)
- An-Liang Xia
- Liver Transplantation Center of the First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China
| | - Xiao-Chen Wang
- Liver Transplantation Center of the First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China
| | - Yi-Jun Lu
- Liver Transplantation Center of the First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China
| | - Xiao-Jie Lu
- Liver Transplantation Center of the First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China
| | - Beicheng Sun
- Liver Transplantation Center of the First Affiliated Hospital and Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210029, P.R. China
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34
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Jin D, Yu X, Chen B, Li Z, Ding J, Zhao X, Qi G. Combined immunotherapy of breast cancer with EGF and VEGF vaccines from DNA shuffling in a mouse model. Immunotherapy 2017; 9:537-553. [PMID: 28509606 DOI: 10.2217/imt-2017-0004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
AIM Development of EGF and VEGF vaccines with high antigenicity for combined immunotherapy of EGF-EGFR signaling-dependent epithelial tumors such as breast cancer. METHOD EGF genes from mouse, human and chicken were randomly assembled to chimeric genes by DNA shuffling, then a chimeric EGF was selected out by PCR, SDS-PAGE and immunization for combined immunotherapy of breast cancer with a previously constructed chimeric VEGF vaccine from shuffling. RESULTS Combined vaccination with chimeric EGF and VEGF from shuffling could induce high titer of antibodies against EGF and VEGF to inhibit tumor growth and angiogenesis, and improve the survival rate of mice with breast cancer. CONCLUSION Combined vaccination with EGF and VEGF from shuffling showed better immunotherapy on EGF-EGFR signaling-dependent epithelial tumors such as breast cancer than the single-agent EGF vaccination.
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Affiliation(s)
- Dong Jin
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xin Yu
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Bing Chen
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhitao Li
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Jia Ding
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiuyun Zhao
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Gaofu Qi
- College of Life Science & Technology, Huazhong Agricultural University, Wuhan 430070, China.,Biomedical Center, Huazhong Agricultural University, Wuhan 430070, China
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35
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Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. Protein Cell 2017; 8:896-925. [PMID: 28466386 PMCID: PMC5712290 DOI: 10.1007/s13238-017-0400-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/15/2017] [Indexed: 12/21/2022] Open
Abstract
Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.
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Abstract
Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.
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37
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Kersh AE, Sasaki M, Cooper LA, Kissick HT, Pollack BP. Understanding the Impact of ErbB Activating Events and Signal Transduction on Antigen Processing and Presentation: MHC Expression as a Model. Front Pharmacol 2016; 7:327. [PMID: 27729860 PMCID: PMC5052536 DOI: 10.3389/fphar.2016.00327] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/06/2016] [Indexed: 12/27/2022] Open
Abstract
Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient's cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity. To realize the promise of 'personalized medicine', it will be important to develop a more integrated understanding of the relationships between oncogenic events and processes governing anti-tumor immunity. One area of investigation to explore such relationships centers on defining how ErbB/HER activation and signal transduction influences antigen processing and presentation.
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Affiliation(s)
- Anna E Kersh
- Medical Scientist Training Program, Emory University School of Medicine Atlanta, GA, USA
| | | | - Lee A Cooper
- Department of Biomedical Informatics, Emory University School of MedicineAtlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of TechnologyAtlanta, GA, USA
| | - Haydn T Kissick
- Department of Urology, Emory University School of Medicine Atlanta, GA, USA
| | - Brian P Pollack
- Atlanta VA Medical CenterDecatur, GA, USA; Department of Dermatology, Emory University School of MedicineAtlanta, GA, USA
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38
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Stylli SS, Luwor RB, Ware TM, Tan F, Kaye AH. Mouse models of glioma. J Clin Neurosci 2015; 22:619-26. [DOI: 10.1016/j.jocn.2014.10.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 10/15/2014] [Indexed: 10/24/2022]
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39
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Biomarkers for glioma immunotherapy: the next generation. J Neurooncol 2015; 123:359-72. [PMID: 25724916 DOI: 10.1007/s11060-015-1746-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 02/16/2015] [Indexed: 12/11/2022]
Abstract
The term "biomarker" historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system-incorporating both immune and tumor parameters-rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm-from single markers to integrated profiles-may offer the key to bringing predictive, personalized immunotherapy to GBM patients.
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Abstract
In this issue of Blood, Casucci et al present an elegant study that describes a potential new target for adoptive cell transfer (ACT), in this case CD44 splice variant 6 (CD44v6), and detail why it may be a good target for ACT and how to manage expected off-tumor/on-target toxicities.
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41
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Sluka P, Davis ID. Cell mates: paracrine and stromal targets for prostate cancer therapy. Nat Rev Urol 2013; 10:441-51. [PMID: 23857181 DOI: 10.1038/nrurol.2013.146] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
After many years of limited treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), multiple systemic therapies are now available, providing patients with significant improvements in survival, symptom control and bone health. Most of the recent advances in this area have been based on better understanding of mCRPC biology, particularly with respect to the key role of androgen receptor signalling. However, most therapies are targeted towards the malignant epithelial cell component of the cancer and it should not be forgotten that cancer cells exist in close and symbiotic relationships with other components of the tumour. Paracrine and stromal signals are often critical to the growth of the cancer and represent new potential therapeutic targets that are separate from the malignant epithelial cells. The stroma produces numerous growth factors, including vascular endothelial growth factor family members, platelet-derived growth factors and fibroblast growth factors, which are all critical for tumour growth. Targeting prostate-cancer-associated fibroblasts in order to destroy the physical and functional scaffold of a cancer is also a logical approach. The interaction between prostate cancer and the immune system remains an active topic of basic and clinical research, with cytokines, chemokines and growth factors being potential targets for therapy. The biology of epithelial-mesenchymal transition and of circulating tumour cells might also provide insight into new therapeutic targets.
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Affiliation(s)
- Pavel Sluka
- Monash University Eastern Health Clinical School, Level 2, 5 Arnold Street, Box Hill, Melbourne, VIC 3128, Australia
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Gupta K, Salunke P. Molecular markers of glioma: an update on recent progress and perspectives. J Cancer Res Clin Oncol 2012; 138:1971-81. [PMID: 23052697 DOI: 10.1007/s00432-012-1323-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 09/17/2012] [Indexed: 02/02/2023]
Abstract
BACKGROUND Significant progress has been made in the molecular diagnostic subtyping of brain tumors especially gliomas. Designing effective tailored therapy remains the cornerstone for delving into the molecular heterogeneity and classification of gliomas. More homogenous tumor populations may lead to more uniform tumor responses in particular molecular constellation. Recent decade has seen a surge of molecular markers of glioma which hold a promise and potential of being strong prognostic, predictive, and diagnostic markers. They are also extremely critical for the stratification of current clinical trails. METHOD Review of the pertinent literature regarding the molecular markers of glioma was performed. Methods of detection of these markers and their clinical relevance are also discussed. RESULTS AND CONCLUSIONS This review provides an update on progress and perspectives of these newest set of biomarkers which can also supplement and refine histological classification and serves as important prognostic and predictive markers; particularly relevant in this aspect are O(6)-methylguanine-DNA methyltransferase promoter methylation, IDH1 mutations, and codeletion of 1p/19q. BRAF fusion/mutations and EGFR amplification provide important clues diagnostically.
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Affiliation(s)
- Kirti Gupta
- Department of Histopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
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43
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Finneman JI, Pozzo MJ. Novel approach for optimization of a ‘difficult’ peptide synthesis by utilizing quantitative reaction monitoring assays. J Pept Sci 2012; 18:511-8. [PMID: 22764082 DOI: 10.1002/psc.2428] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 05/09/2012] [Accepted: 05/21/2012] [Indexed: 11/09/2022]
Affiliation(s)
- Jari I. Finneman
- Department of Bioprocess Research and Development; Pfizer Global Biologics; 700 Chesterfield Parkway West; Chesterfield; MO; 63017; USA
| | - Mark J. Pozzo
- Department of Bioprocess Research and Development; Pfizer Global Biologics; 700 Chesterfield Parkway West; Chesterfield; MO; 63017; USA
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44
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Del Vecchio CA, Li G, Wong AJ. Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 2012; 11:133-44. [PMID: 22309662 DOI: 10.1586/erv.11.177] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common and deadly of the human brain cancers. The EGF receptor is often amplified in GBM and provides a potential therapeutic target. However, targeting the normal receptor is complicated by its nearly ubiquitous and high level of expression in certain tissues. A naturally occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively active variant originally identified in a high percentage of brain cancer cases, and more importantly is rarely found in normal tissue. A peptide vaccine, rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon 1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy in preclinical models. Recent Phase II clinical trials in patients with newly diagnosed GBM have shown EGFRvIII-specific immune responses and significantly increased time to progression and overall survival in those receiving vaccine therapy, as compared with published results for standard of care. Rindopepimut therefore represents a very promising therapy for patients with GBM.
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45
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Schutt C, Bumm K, Mirandola L, Bernardini G, Cunha ND, Tijani L, Nguyen D, Cordero J, Jenkins MR, Cobos E, Kast WM, Chiriva-Internati M. Immunological treatment options for locoregionally advanced head and neck squamous cell carcinoma. Int Rev Immunol 2012; 31:22-42. [PMID: 22251006 DOI: 10.3109/08830185.2011.637253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Patients with squamous cell carcinoma of the head and neck (HNSCC) are usually treated by a multimodal approach with surgery and/or radiochemotherapy as the mainstay of local-regional treatment in cases with advanced disease. Both chemotherapy and radiation therapy have the disadvantage of causing severe side effects, while the clinical outcome of patients diagnosed with HNSCC has remained essentially unchanged over the last decade. The potential of immunotherapy is still largely unexplored. Here the authors review the current status of the art and discuss the future challenges in HNSCC treatment and prevention.
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Affiliation(s)
- Christopher Schutt
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; and Department of Surgery at the Division of Otolaryngology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Klaus Bumm
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA
| | - Leonardo Mirandola
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; Laura W. Bush Institute for Women's Health and Center for Women's Health and Gender-Based Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA; and Department of Medicine Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy
| | - Giovanni Bernardini
- Department of Biotechnology and Molecular Science, University of Insubria, Varese, Italy
| | - Nicholas D' Cunha
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA
| | - Lukman Tijani
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA
| | - Diane Nguyen
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA
| | - Joehassin Cordero
- Division of Surgery, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA
| | - Marjorie R Jenkins
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; and Laura W. Bush Institute for Women's Health and Center for Women's Health and Gender-Based Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - Everardo Cobos
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; and Laura W. Bush Institute for Women's Health and Center for Women's Health and Gender-Based Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - W Martin Kast
- Department of Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA; Department of Obstetrics & Gynecology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA; and Cancer Research Center of Hawaii, University of Hawaii at Manao, Honolulu, Hawaii, USA
| | - Maurizio Chiriva-Internati
- Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; Division of Surgery, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, USA; and Laura W. Bush Institute for Women's Health and Center for Women's Health and Gender-Based Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
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46
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Li G, Mitra SS, Monje M, Henrich KN, Bangs CD, Nitta RT, Wong AJ. Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas. J Neurooncol 2012; 108:395-402. [PMID: 22382786 DOI: 10.1007/s11060-012-0842-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Accepted: 02/20/2012] [Indexed: 01/14/2023]
Abstract
Despite numerous clinical trials over the past 2 decades, the overall survival for children diagnosed with diffuse intrinsic pontine glioma (DIPG) remains 9-10 months. Radiation therapy is the only treatment with proven effect and novel therapies are needed. Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the epidermal growth factor receptor and is expressed in many tumor types but is rarely found in normal tissue. A peptide vaccine targeting EGFRvIII is currently undergoing investigation in phase 3 clinical trials for the treatment of newly diagnosed glioblastoma (GBM), the tumor in which this variant receptor was first discovered. In this study, we evaluated EGFRvIII expression in pediatric DIPG samples using immunohistochemistry with a double affinity purified antibody raised against the EGFRvIII peptide. Staining of pediatric DIPG histological samples revealed expression in 4 of 9 cases and the pattern of staining was consistent with what has been seen in EGFRvIII transfected cells as well as GBMs from adult trials. In addition, analysis of tumor samples collected immediately post mortem and of DIPG cells in culture by RT-PCR, western blot analysis, and flow cytometry confirmed EGFRvIII expression. We were therefore able to detect EGFRvIII expression in 6 of 11 DIPG cases. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors.
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Affiliation(s)
- Gordon Li
- Department of Neurosurgery, Stanford University Medical Center, Stanford, CA 94305, USA.
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47
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Parney IF. Basic Concepts in Glioma Immunology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 746:42-52. [DOI: 10.1007/978-1-4614-3146-6_4] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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48
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Nitta RT, Li G. The invasive nature of glioblastoma. World Neurosurg 2011; 80:279-80. [PMID: 22120249 DOI: 10.1016/j.wneu.2011.09.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 09/10/2011] [Indexed: 11/19/2022]
Affiliation(s)
- Ryan T Nitta
- Brain Tumor Research Laboratories, Department of Neurosurgery, Stanford University Medical School, Stanford, California, USA
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49
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Zhu H, Lo HW. The Human Glioma-Associated Oncogene Homolog 1 (GLI1) Family of Transcription Factors in Gene Regulation and Diseases. Curr Genomics 2011; 11:238-45. [PMID: 21119888 PMCID: PMC2930663 DOI: 10.2174/138920210791233108] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Revised: 04/07/2010] [Accepted: 04/07/2010] [Indexed: 12/30/2022] Open
Abstract
Sonic hedgehog (Shh) signaling is critically important for embryogenesis and other cellular processes in which GLI transcription factors mediate the terminal effects of the pathway. GLI1, in particular, plays a significant role in human cancers. Consequently, GLI1 and its upstream positive regulator Smoothened (SMO) are important targets of anti-cancer therapy and several SMO-targeted small molecule inhibitors are being evaluated clinically. Emerging exciting evidence reveals a high level of complexity that lies within the GLI1-mediated pathway. For example, a recent study provided evidence linking the polymorphic GLI1 variants Q1100/E1100 to chronic inflammatory bowel diseases. Two recent reports uncovered the existence of two novel human GLI1 isoforms that differ structurally and functionally from the wild-type GLI1 identified over two decades ago. Interestingly, although both are products of alternative splicing, GLI1∆N and tGLI1 (truncated GLI1) isoforms are predominantly expressed in normal and malignant tissues, respectively. In addition to these important discoveries, gene expression profiling studies have identified a number of novel wild-type GLI1 and tGLI1 target genes, linking wild-type GLI1 to tumor progression and therapeutic resistance, and tGLI1 to tumor invasion and migration. In light of these new insights, this review will provide a comprehensive overview on GLI1 polymorphisms and the three members of the GLI1 family of proteins, and their impacts on human diseases, including, cancers.
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Affiliation(s)
- Hu Zhu
- Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine
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50
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Denholt CL, Binderup T, Stockhausen MT, Poulsen HS, Spang-Thomsen M, Hansen PR, Gillings N, Kjær A. Evaluation of 4-[18F]fluorobenzoyl-FALGEA-NH2 as a positron emission tomography tracer for epidermal growth factor receptor mutation variant III imaging in cancer. Nucl Med Biol 2011; 38:509-15. [DOI: 10.1016/j.nucmedbio.2010.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Revised: 11/26/2010] [Accepted: 11/28/2010] [Indexed: 10/18/2022]
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