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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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Mata-Molanes JJ, Alserawan L, España C, Guijarro C, López-Pecino A, Calderón H, Altuna A, Pérez-Amill L, Klein-González N, Fernández de Larrea C, González-Navarro EA, Delgado J, Juan M, Castella M. A Quantitative Approach to Potency Testing for Chimeric Antigen Receptor-Encoding Lentiviral Vectors and Autologous CAR-T Cell Products, Using Flow Cytometry. Pharmaceutics 2025; 17:303. [PMID: 40142967 PMCID: PMC11944512 DOI: 10.3390/pharmaceutics17030303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/13/2025] [Accepted: 02/22/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Potency testing of clinical-grade lentiviral vectors (LVVs) is critical to support a drug's commercial approval. Careful consideration should be paid to the development of a suitable potency test during the drug's clinical development. We aimed to develop an affordable, quantitative test for our CAR19-LVV, based on a measure of transgene's functional activity. Methods: Several indicators of functional activity of CAR19-LVV were explored in a co-culture setting of CAR-transduced Jurkat cells and CD19-expressing target cells. The selected assay was further developed and subjected to validation. Assay's adaptability to other CAR-encoding LVV and autologous CAR-T cell products was also investigated. Results: Measure of CD69 expression on the membrane of Jurkat-CAR-expressing cells is a specific indicator of CAR functionality. Quantification of CD69 in terms of mean fluorescence intensity (MFI), coupled with an intra-assay standard curve calibration, allows for a quantitative assay with high precision, specificity, robustness, linearity and accuracy. The assay has also shown optimal performance for a CARBCMA-LVV product. Importantly, we show that in primary T cells, CD69 expression reflects CAR-T cell cytotoxicity. After adaptation, we have applied a CD69-based potency test, with simultaneous measurement of CAR-T cell cytotoxicity, to autologous CAR-T cell products, demonstrating the assay's specificity also in this context. Conclusions: We developed a validated, in vitro cell-based potency test, using a quantitative flow-cytometry method, for our CAR19-LVV. The assay is based on the detection of T-cell activation upon CAR binding to antigen, which is a measure of transgene functionality. The assay was easily adapted to another CAR-encoding LVV, targeting a different molecule. Furthermore, the same assay principle can be applied in the context of autologous CAR-T cell products. The quantitative CD69 potency assay shows reduced variability among autologous products compared to the IFNγ assay and allows for simultaneous evaluation of traditional semi-quantitative cytotoxicity, thereby directly evaluating the drug's mechanism of action (MoA) in the same assay.
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Affiliation(s)
- Juan José Mata-Molanes
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Leticia Alserawan
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Carolina España
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
| | - Carla Guijarro
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
| | - Ana López-Pecino
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
- School of Medicine, Universitat de Barcelona (UB), 08036 Barcelona, Spain; (C.F.d.L.); (J.D.)
| | - Hugo Calderón
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Ane Altuna
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
- School of Medicine, Universitat de Barcelona (UB), 08036 Barcelona, Spain; (C.F.d.L.); (J.D.)
| | - Lorena Pérez-Amill
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Nela Klein-González
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Carlos Fernández de Larrea
- School of Medicine, Universitat de Barcelona (UB), 08036 Barcelona, Spain; (C.F.d.L.); (J.D.)
- Department of Hematology, Institute of Cancer and Blood Diseases, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain
- Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain
| | - Europa Azucena González-Navarro
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
| | - Julio Delgado
- School of Medicine, Universitat de Barcelona (UB), 08036 Barcelona, Spain; (C.F.d.L.); (J.D.)
- Department of Hematology, Institute of Cancer and Blood Diseases, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain
- Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain
| | - Manel Juan
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
- School of Medicine, Universitat de Barcelona (UB), 08036 Barcelona, Spain; (C.F.d.L.); (J.D.)
| | - Maria Castella
- Department of Immunology, CDB, Hospital Clinic de Barcelona (HCB), 08036 Barcelona, Spain; (J.J.M.-M.); (L.A.); (C.E.); (C.G.); (H.C.); (E.A.G.-N.); (M.J.)
- Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses Group, Fundació Clínic-IDIBAPS, 08036 Barcelona, Spain; (A.L.-P.); (A.A.); (L.P.-A.); (N.K.-G.)
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Song Y, Wang Y, Man J, Xu Y, Zhou G, Shen W, Chao Y, Yang K, Pei P, Hu L. Chimeric Antigen Receptor Cells Solid Tumor Immunotherapy Assisted by Biomaterials Tools. ACS APPLIED MATERIALS & INTERFACES 2025; 17:10246-10264. [PMID: 39903799 DOI: 10.1021/acsami.4c20275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Chimeric antigen receptor (CAR) immune cell therapies have revolutionized oncology, particularly in hematological malignancies, yet their efficacy against solid tumors remains limited due to challenges such as dense stromal barriers and immunosuppressive microenvironments. With advancements in nanobiotechnology, researchers have developed various strategies and methods to enhance the CAR cell efficacy in solid tumor treatment. In this Review, we first outline the structure and mechanism of CAR-T (T, T cell), CAR-NK (NK, natural killer), and CAR-M (M, macrophage) cell therapies and deeply analyze the potential of these cells in the treatment of solid tumors and the challenges they face. Next, we explore how biomaterials can optimize these treatments by improving the tumor microenvironment, controlling CAR cell release, promoting cell infiltration, and enhancing efficacy. Finally, we summarize the current challenges and potential solutions, emphasize the effective combination of biomaterials and CAR cell therapy, and look forward to its future clinical application and treatment strategies. This Review provides important theoretical perspectives and practical guidance for the future development of more effective solid tumor treatment strategies.
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Affiliation(s)
- Yujie Song
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
| | - Yifan Wang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
| | - Jianping Man
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
| | - Yihua Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
| | - Guangming Zhou
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Wenhao Shen
- Department of Oncology, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou, Jiangsu 225300, China
| | - Yu Chao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China
| | - Kai Yang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
| | - Pei Pei
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Lin Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215123, China
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Pu J, Liu T, Sharma A, Jiang L, Wei F, Ren X, Schmidt-Wolf IGH, Hou J. Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma. Exp Hematol Oncol 2024; 13:105. [PMID: 39468695 PMCID: PMC11514856 DOI: 10.1186/s40164-024-00576-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024] Open
Abstract
The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.
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Affiliation(s)
- Jingjing Pu
- Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn, University Hospital Bonn, 53127, Bonn, NRW, Germany
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Ting Liu
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, NRW, Germany
| | - Amit Sharma
- Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn, University Hospital Bonn, 53127, Bonn, NRW, Germany
| | - Liping Jiang
- Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, Jiangsu, China
| | - Feng Wei
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300070, China
| | - Xiubao Ren
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300070, China.
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn, University Hospital Bonn, 53127, Bonn, NRW, Germany.
| | - Jian Hou
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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5
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Wittling MC, Cole AC, Brammer B, Diatikar KG, Schmitt NC, Paulos CM. Strategies for Improving CAR T Cell Persistence in Solid Tumors. Cancers (Basel) 2024; 16:2858. [PMID: 39199630 PMCID: PMC11352972 DOI: 10.3390/cancers16162858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/09/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
CAR T cells require optimization to be effective in patients with solid tumors. There are many barriers affecting their ability to succeed. One barrier is persistence, as to achieve an optimal antitumor response, infused CAR T cells must engraft and persist. This singular variable is impacted by a multitude of factors-the CAR T cell design, lymphodepletion regimen used, expansion method to generate the T cell product, and more. Additionally, external agents can be utilized to augment CAR T cells, such as the addition of novel cytokines, pharmaceutical drugs that bolster memory formation, or other agents during either the ex vivo expansion process or after CAR T cell infusion to support them in the oppressive tumor microenvironment. This review highlights many strategies being used to optimize T cell persistence as well as future directions for improving the persistence of infused cells.
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Affiliation(s)
- Megen C. Wittling
- Department of Surgery/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
- School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Anna C. Cole
- Department of Surgery/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
| | - Brianna Brammer
- School of Medicine, Emory University, Atlanta, GA 30322, USA
- Department of Otolaryngology, Emory University, Atlanta, GA 30322, USA
| | - Kailey G. Diatikar
- Department of Surgery/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
| | - Nicole C. Schmitt
- Department of Otolaryngology, Emory University, Atlanta, GA 30322, USA
| | - Chrystal M. Paulos
- Department of Surgery/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
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Wei F, Liu H, Wang Y, Li Y, Han S. Engineering macrophages and their derivatives: A new hope for antitumor therapy. Biomed Pharmacother 2024; 177:116925. [PMID: 38878637 DOI: 10.1016/j.biopha.2024.116925] [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: 04/11/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 07/28/2024] Open
Abstract
Macrophages are central to the immune system and are found in nearly all tissues. Recently, the development of therapies based on macrophages has attracted significant interest. These therapies utilize macrophages' key roles in immunity, their ability to navigate biological barriers, and their tendency to accumulate in tumors. This review explores the advancement of macrophage-based treatments. We discuss the bioengineering of macrophages for improved anti-tumor effects, the use of CAR macrophage therapy for targeting cancer cells, and macrophages as vehicles for therapeutic delivery. Additionally, we examine engineered macrophage products, like extracellular vesicles and membrane-coated nanoparticles, for their potential in precise and less toxic tumor therapy. Challenges in moving these therapies from research to clinical practice are also highlighted. The aim is to succinctly summarize the current status, challenges, and future directions of engineered macrophages in cancer therapy.
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Affiliation(s)
- Fang Wei
- Department of General surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province 110032, China
| | - Haiyang Liu
- Department of General surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province 110032, China
| | - Yuxiao Wang
- Anesthesia Department, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province 110032, China
| | - Yan Li
- Department of General surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province 110032, China.
| | - Shuo Han
- Department of Cardiology, the Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province 110032, China.
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Serrano S, Barrio R, Martínez-Rubio Á, Belmonte-Beitia J, Pérez-García VM. Understanding the role of B cells in CAR T-cell therapy in leukemia through a mathematical model. CHAOS (WOODBURY, N.Y.) 2024; 34:083142. [PMID: 39191245 DOI: 10.1063/5.0206341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024]
Abstract
Chimeric antigen receptor T (CAR T) cell therapy has been proven to be successful against a variety of leukemias and lymphomas. This paper undertakes an analytical and numerical study of a mathematical model describing the competition of CAR T, leukemia, tumor, and B cells. Considering its significance in sustaining anti-CD19 CAR T-cell stimulation, a B-cell source term is integrated into the model. Through stability and bifurcation analyses, the potential for tumor eradication, contingent on the continuous influx of B cells, has been revealed, showing a transcritical bifurcation at a critical B-cell input. Additionally, an almost heteroclinic cycle between equilibrium points is identified, providing a theoretical basis for understanding disease relapse. Analyzing the oscillatory behavior of the system, the time-dependent dynamics of CAR T cells and leukemic cells can be approximated, shedding light on the impact of initial tumor burden on therapeutic outcomes. In conclusion, the study provides insights into CAR T-cell therapy dynamics for acute lymphoblastic leukemias, offering a theoretical foundation for clinical observations and suggesting avenues for future immunotherapy modeling research.
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Affiliation(s)
- Sergio Serrano
- IUMA, CoDy and Department of Applied Mathematics, Universidad de Zaragoza, Zaragoza 50009, Spain
| | - Roberto Barrio
- IUMA, CoDy and Department of Applied Mathematics, Universidad de Zaragoza, Zaragoza 50009, Spain
| | - Álvaro Martínez-Rubio
- Department of Mathematics, Universidad de Cádiz, Puerto Real, Cádiz 11510, Spain
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz 11002, Spain
| | - Juan Belmonte-Beitia
- Mathematical Oncology Laboratory (MOLAB), Departament of Mathematics, Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Ciudad Real 13071, Spain
| | - Víctor M Pérez-García
- Mathematical Oncology Laboratory (MOLAB), Departament of Mathematics, Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Ciudad Real 13071, Spain
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Utkarsh K, Srivastava N, Kumar S, Khan A, Dagar G, Kumar M, Singh M, Haque S. CAR-T cell therapy: a game-changer in cancer treatment and beyond. Clin Transl Oncol 2024; 26:1300-1318. [PMID: 38244129 DOI: 10.1007/s12094-023-03368-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/04/2023] [Indexed: 01/22/2024]
Abstract
In recent years, cancer has become one of the primary causes of mortality, approximately 10 million deaths worldwide each year. The most advanced, chimeric antigen receptor (CAR) T cell immunotherapy has turned out as a promising treatment for cancer. CAR-T cell therapy involves the genetic modification of T cells obtained from the patient's blood, and infusion back to the patients. CAR-T cell immunotherapy has led to a significant improvement in the remission rates of hematological cancers. CAR-T cell therapy presently limited to hematological cancers, there are ongoing efforts to develop additional CAR constructs such as bispecific CAR, tandem CAR, inhibitory CAR, combined antigens, CRISPR gene-editing, and nanoparticle delivery. With these advancements, CAR-T cell therapy holds promise concerning potential to improve upon traditional cancer treatments such as chemotherapy and radiation while reducing associated toxicities. This review covers recent advances and advantages of CAR-T cell immunotherapy.
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Affiliation(s)
- Kumar Utkarsh
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Namita Srivastava
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Sachin Kumar
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Azhar Khan
- Faculty of Applied Science and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Gunjan Dagar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Mukesh Kumar
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Mayank Singh
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Shabirul Haque
- Department of Autoimmune Diseases, Feinstein Institute for Medical Research, Northwell Health, 350, Community Drive, Manhasset, NY, 11030, USA.
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Hernandez-Gamarra M, Salgado-Roo A, Dominguez E, Goiricelaya Seco EM, Veiga-Rúa S, Pedrera-Garbayo LF, Carracedo Á, Allegue C. CARTAR: a comprehensive web tool for identifying potential targets in chimeric antigen receptor therapies using TCGA and GTEx data. Brief Bioinform 2024; 25:bbae326. [PMID: 38975894 PMCID: PMC11229032 DOI: 10.1093/bib/bbae326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/24/2024] [Accepted: 06/26/2024] [Indexed: 07/09/2024] Open
Abstract
Chimeric antigen receptor (CAR) therapy has emerged as a ground-breaking advancement in cancer treatment, harnessing the power of engineered human immune cells to target and eliminate cancer cells. The escalating interest and investment in CAR therapy in recent years emphasize its profound significance in clinical research, positioning it as a rapidly expanding frontier in the field of personalized cancer therapies. A crucial step in CAR therapy design is choosing the right target as it determines the therapy's effectiveness, safety and specificity against cancer cells, while sparing healthy tissues. Herein, we propose a suite of tools for the identification and analysis of potential CAR targets leveraging expression data from The Cancer Genome Atlas and Genotype-Tissue Expression Project, which are implemented in CARTAR website. These tools focus on pinpointing tumor-associated antigens, ensuring target selectivity and assessing specificity to avoid off-tumor toxicities and can be used to rationally designing dual CARs. In addition, candidate target expression can be explored in cancer cell lines using the expression data for the Cancer Cell Line Encyclopedia. To our best knowledge, CARTAR is the first website dedicated to the systematic search of suitable candidate targets for CAR therapy. CARTAR is publicly accessible at https://gmxenomica.github.io/CARTAR/.
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Affiliation(s)
- Miguel Hernandez-Gamarra
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
| | - Alba Salgado-Roo
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
| | - Eduardo Dominguez
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
| | | | - Sara Veiga-Rúa
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
| | - Lucía F Pedrera-Garbayo
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
| | - Ángel Carracedo
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
- Fundación Pública Galega de Medicina Xenómica (FPGMX), Travesía da Choupana, 15706 A Coruña, Spain
- CB06/07/0088, Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Av. Monforte de Lemos, 28029 Madrid, Spain
| | - Catarina Allegue
- Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Av. Barcelona, 15706 A Coruña, Spain
- C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Travesía da Choupana, 15706 A Coruña, Spain
- CB06/07/0088, Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Av. Monforte de Lemos, 28029 Madrid, Spain
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10
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Savoldo B, Grover N, Dotti G. CAR T cells for hematological malignancies. J Clin Invest 2024; 134:e177160. [PMID: 38226627 PMCID: PMC10786683 DOI: 10.1172/jci177160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024] Open
Affiliation(s)
- Barbara Savoldo
- Lineberger Comprehensive Cancer Center
- Department of Pediatrics
| | - Natalie Grover
- Lineberger Comprehensive Cancer Center
- Department of Medicine, and
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center
- Department of Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Huang XD, Chen YW, Tian L, Du L, Cheng XC, Lu YX, Lin DD, Xiao FJ. NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis. J Cancer Res Clin Oncol 2024; 150:8. [PMID: 38195952 PMCID: PMC10776698 DOI: 10.1007/s00432-023-05540-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/29/2023] [Indexed: 01/11/2024]
Abstract
BACKGROUND NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. METHODS Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. RESULTS We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. CONCLUSION Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.
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Affiliation(s)
- Xiao-Dong Huang
- Department of General Surgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, People's Republic of China
| | - Yong-Wei Chen
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Lv Tian
- School of Nursing, Jilin University, Changchun, 130015, People's Republic of China
| | - Li Du
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Xiao-Chen Cheng
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Yu-Xin Lu
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Dong-Dong Lin
- Department of General Surgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, People's Republic of China.
| | - Feng-Jun Xiao
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
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12
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Li X, Chen Z, Ye W, Yu J, Zhang X, Li Y, Niu Y, Ran S, Wang S, Luo Z, Zhao J, Hao Y, Zong J, Xia C, Xia J, Wu J. High-throughput CRISPR technology: a novel horizon for solid organ transplantation. Front Immunol 2024; 14:1295523. [PMID: 38239344 PMCID: PMC10794540 DOI: 10.3389/fimmu.2023.1295523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/12/2023] [Indexed: 01/22/2024] Open
Abstract
Organ transplantation is the gold standard therapy for end-stage organ failure. However, the shortage of available grafts and long-term graft dysfunction remain the primary barriers to organ transplantation. Exploring approaches to solve these issues is urgent, and CRISPR/Cas9-based transcriptome editing provides one potential solution. Furthermore, combining CRISPR/Cas9-based gene editing with an ex vivo organ perfusion system would enable pre-implantation transcriptome editing of grafts. How to determine effective intervention targets becomes a new problem. Fortunately, the advent of high-throughput CRISPR screening has dramatically accelerated the effective targets. This review summarizes the current advancements, utilization, and workflow of CRISPR screening in various immune and non-immune cells. It also discusses the ongoing applications of CRISPR/Cas-based gene editing in transplantation and the prospective applications of CRISPR screening in solid organ transplantation.
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Affiliation(s)
- Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC) Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC) Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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13
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Wang Y, Li YR. Harnessing Chimeric Antigen Receptor-engineered Invariant Natural Killer T Cells: Therapeutic Strategies for Cancer and the Tumor Microenvironment. Curr Pharm Biotechnol 2024; 25:2001-2011. [PMID: 38310449 DOI: 10.2174/0113892010265228231116073012] [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: 07/04/2023] [Revised: 09/17/2023] [Accepted: 10/04/2023] [Indexed: 02/05/2024]
Abstract
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has emerged as a revolutionary approach for cancer treatment, especially for hematologic cancers. However, CAR-T therapy has some limitations, including cytokine release syndrome (CRS), immune cellassociated neurologic syndrome (ICANS), and difficulty in targeting solid tumors and delivering allogeneic cell therapy due to graft-versus-host disease (GvHD). Therefore, it is important to explore other cell sources for CAR engineering. Invariant natural killer T (iNKT) cells are a potential target, as they possess powerful antitumor ability and do not recognize mismatched major histocompatibility complexes (MHCs) and protein antigens, thus avoiding the risk of GvHD. CAR-engineered iNKT (CAR-iNKT) cell therapy offers a promising new approach to cancer immunotherapy by overcoming the drawbacks of CAR-T cell therapy while retaining potent antitumor capabilities. This review summarizes the current CAR-iNKT cell products, their functions and phenotypes, and their potential for off-the-shelf cancer immunotherapy.
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Affiliation(s)
- Yiqing Wang
- Department of Chemistry, Biochemistry, University of Washington, Seattle, WA 98105, USA
| | - Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
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14
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Stock S, Klüver AK, Fertig L, Menkhoff VD, Subklewe M, Endres S, Kobold S. Mechanisms and strategies for safe chimeric antigen receptor T-cell activity control. Int J Cancer 2023; 153:1706-1725. [PMID: 37350095 DOI: 10.1002/ijc.34635] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/07/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.
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Affiliation(s)
- Sophia Stock
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- Department of Medicine III, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Anna-Kristina Klüver
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Luisa Fertig
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Vivien D Menkhoff
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Marion Subklewe
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
| | - Stefan Endres
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
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15
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Zappa E, Vitali A, Anders K, Molenaar JJ, Wienke J, Künkele A. Adoptive cell therapy in paediatric extracranial solid tumours: current approaches and future challenges. Eur J Cancer 2023; 194:113347. [PMID: 37832507 PMCID: PMC10695178 DOI: 10.1016/j.ejca.2023.113347] [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: 07/17/2023] [Revised: 09/03/2023] [Accepted: 09/09/2023] [Indexed: 10/15/2023]
Abstract
Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT). Particularly, ACT using T cells equipped with chimeric antigen receptors (CARs) has moved into the spotlight in clinical studies. However, the efficacy of ACT is challenged by ACT-intrinsic factors, like lack of activation or T cell exhaustion, as well as immune evasion strategies of paediatric solid tumours, such as their highly immunosuppressive microenvironment. Novel strategies, including ACT using innate-like lymphocytes, innovative cell engineering techniques, and ACT combination therapies, are being developed and will be crucial to overcome these challenges. Here, we discuss the main classes of ACT for the treatment of paediatric extracranial solid tumours, reflect on the available preclinical and clinical evidence supporting promising strategies, and address the challenges that ACT is still facing. Ultimately, we highlight state-of-the-art developments and opportunities for new therapeutic options, which hold great potential for improving outcomes in this challenging patient population.
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Affiliation(s)
- Elisa Zappa
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Alice Vitali
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.
| | - Kathleen Anders
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan J Molenaar
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Judith Wienke
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
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16
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Lam N, Finney R, Yang S, Choi S, Wu X, Cutmore L, Andrade J, Huang L, Amatya C, Cam M, Kochenderfer JN. Development of a bicistronic anti-CD19/CD20 CAR construct including abrogation of unexpected nucleic acid sequence deletions. Mol Ther Oncolytics 2023; 30:132-149. [PMID: 37654973 PMCID: PMC10465854 DOI: 10.1016/j.omto.2023.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/17/2023] [Indexed: 09/02/2023] Open
Abstract
To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct encoding an anti-CD19 CAR and an anti-CD20 CAR. We detected deletions from the expected bicistronic construct sequence in a minority of transcripts by mRNA sequencing. Loss of bicistronic construct transgene DNA was also detected. Deletions of sequence were present at much higher frequencies in transduced T cell mRNA versus gamma-retroviral vector RNA. We concluded that these deletions were caused by intramolecular template switching of the reverse transcriptase enzyme during reverse transcription of gamma-retroviral vector RNA into transgene DNA of transduced T cells. Intramolecular template switching was driven by repeated regions of highly similar nucleic acid sequence within CAR sequences. We optimized the sequence of the bicistronic CAR construct to reduce repeated regions of highly similar sequences. This optimization nearly eliminated sequence deletions. This work shows that repeated regions of highly similar nucleic acid sequence must be avoided in complex CAR constructs. We further optimized the bicistronic construct by lengthening the linker of the anti-CD20 single-chain variable fragment. This modification increased CD20-specific interleukin-2 release and reduced CD20-specific activation-induced cell death. We selected an optimized anti-CD19/CD20 bicistronic construct for clinical development.
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Affiliation(s)
- Norris Lam
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
| | - Richard Finney
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD, USA
| | - Shicheng Yang
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
| | - Stephanie Choi
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
| | - Xiaolin Wu
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Lauren Cutmore
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
| | | | - Lei Huang
- Kite, A Gilead Company, Santa Monica, CA, USA
| | - Christina Amatya
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
| | - Margaret Cam
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD, USA
| | - James N. Kochenderfer
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA
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17
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Liao C, Wang Y, Huang Y, Duan Y, Liang Y, Chen J, Jiang J, Shang K, Zhou C, Gu Y, Liu N, Zeng X, Gao X, Tang Y, Sun J. CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207394. [PMID: 37485647 PMCID: PMC10520621 DOI: 10.1002/advs.202207394] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 06/27/2023] [Indexed: 07/25/2023]
Abstract
The robust and stable expression of CD38 in T-cell acute lymphoblastic leukemia (T-ALL) blasts makes CD38 chimeric antigen receptor (CAR)-T/natural killer (NK) a potential therapy for T-ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR-T/NK cells. Here a "2-in-1" gene editing strategy is developed to generate fratricide-resistant locus-specific CAR-T/NK cells. CD38-specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI ) or exogenous EF1α promoter (CD38KO/KI EF1α). CD38 knockout reduces fratricide and allows the expansion of CAR-T cells. Meanwhile, CD38KO/KI EF1α results in higher CAR expression than CD38KO/KI in both CAR-T and CAR-NK cells. In a mouse T-ALL model, CD38KO/KI EF1α CAR-T cells eradicate tumors better than CD38KO/KI CAR-T cells. Surprisingly, CD38KO/KI CAR-NK cells show superior tumor control than CD38KO/KI EF1α CAR-NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR-T and CAR-NK cells differently. Therefore, these results support the efficacy of CD38 CAR-T/NK against T-ALL and demonstrate that the "2-in-1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation.
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Affiliation(s)
- Chan Liao
- Department of Hematology‐oncologyChildren's HospitalZhejiang University School of MedicinePediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province National Clinical Research Center for Child HealthHangzhou310003China
| | - Yajie Wang
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
| | - Yanjie Huang
- Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhou310058China
- School of Basic Medical SciencesFudan UniversityShanghai200032China
| | - Yanting Duan
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
| | - Yan Liang
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
| | - Jiangqing Chen
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
| | - Jie Jiang
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
| | - Kai Shang
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
| | - Chun Zhou
- School of Public Health and Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou310058China
| | - Ying Gu
- Institute of Genetics, Zhejiang University and Department of GeneticsZhejiang University school of medicineHangzhou310058China
| | - Nan Liu
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
| | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesFirst Affiliated HospitalZhejiang University School of MedicineHangzhou310058China
| | - Xiaofei Gao
- Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhou310058China
| | - Yongmin Tang
- Department of Hematology‐oncologyChildren's HospitalZhejiang University School of MedicinePediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province National Clinical Research Center for Child HealthHangzhou310003China
| | - Jie Sun
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhou311121China
- Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell BiologyZhejiang University School of MedicineHangzhou310058China
- Institute of HematologyZhejiang University & Zhejiang Engineering Laboratory for Stem Cell and ImmunotherapyHangzhou310058China
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18
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Zhang J, Xu L, Zhang J, Liu Y, Li X, Ren T, Liu H. Pan-cancer analysis of the prognostic and immunological role of matrix metalloproteinase 9. Medicine (Baltimore) 2023; 102:e34499. [PMID: 37505149 PMCID: PMC10378727 DOI: 10.1097/md.0000000000034499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/15/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023] Open
Abstract
Matrix metalloproteinase 9 (MMP9), a zinc ion-dependent endopeptidase, is one of the most complex matrix metalloproteinases in the gelatinase family. During tissue remodeling, MMP9 leads to gelatin and collagen degradation, which in turn promotes tumor invasion and metastasis. However, comprehensive pan-cancer analysis has not been performed for MMP9. In addition, the diagnostic and prognostic value of MMP9 as a cancer biomarker remain poorly understood, as well as the utility of MMP9 expression as a predictor of immunological responses. Based on a comprehensive analysis of bioinformatics information, we investigated MMP9 expression in different cancers, correlations between MMP9 expression and cancer prognosis and gene mutations, and relationships between MMP9 expression and immune cell infiltration. Our results indicated that MMP9 was highly expressed in most malignant cancers. MMP9 expression was significantly positively or negatively associated with the clinical prognoses of patients with different kinds of cancer. Furthermore, MMP9 expression significantly correlated with infiltrating cells and the expression levels of immune checkpoint genes. This pan-cancer analysis provides comprehensive information on the potential value of MMP9 as a theranostic biomarker.
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Affiliation(s)
- Jie Zhang
- Clinical Medical School, Chengdu Medical College, Chengdu, China
- Oncology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Key Clinical Specialty of Sichuan Province (Oncology Department), The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Lei Xu
- Clinical Medical School, Chengdu Medical College, Chengdu, China
- Gynecology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jingjun Zhang
- Oncology Department, The People’s Hospital of Jianyang City, Chengdu, China
| | - Ying Liu
- Clinical Medical School, Chengdu Medical College, Chengdu, China
| | - Xiang Li
- Clinical Medical School, Chengdu Medical College, Chengdu, China
| | - Tao Ren
- Clinical Medical School, Chengdu Medical College, Chengdu, China
- Oncology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Key Clinical Specialty of Sichuan Province (Oncology Department), The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Hairong Liu
- Clinical Medical School, Chengdu Medical College, Chengdu, China
- Science and Technology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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Christodoulou I, Solomou EE. A Panorama of Immune Fighters Armored with CARs in Acute Myeloid Leukemia. Cancers (Basel) 2023; 15:cancers15113054. [PMID: 37297016 DOI: 10.3390/cancers15113054] [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: 04/14/2023] [Revised: 05/28/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML.
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Affiliation(s)
- Ilias Christodoulou
- Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Internal Medicine, University of Patras Medical School, 26500 Rion, Greece
| | - Elena E Solomou
- Department of Internal Medicine, University of Patras Medical School, 26500 Rion, Greece
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20
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Abstract
T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of immunotherapy. Recent work has also shown that NK cells play an important role in recruiting dendritic cells to tumors and thus enhance induction of CD8 T cell responses, while IL-2 secreted by T cells activates NK cells. Targeting of immune evasion mechanisms from the activating NKG2D receptor and its MICA and MICB ligands on tumor cells offers opportunities for therapeutic intervention. Interestingly, T cells and NK cells share several important inhibitory and activating receptors that can be targeted to enhance T cell- and NK cell-mediated immunity. These inhibitory receptor-ligand systems include CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E. We also discuss emerging therapeutic strategies based on inhibitory and activating cytokines that profoundly impact the function of both lymphocyte populations within tumors.
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Affiliation(s)
- Oleksandr Kyrysyuk
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
| | - Kai W Wucherpfennig
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
- Department of Neurology, Brigham & Women's Hospital, Boston, Massachusetts, USA
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA
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21
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Stuckey R, Luzardo Henríquez H, de la Nuez Melian H, Rivero Vera JC, Bilbao-Sieyro C, Gómez-Casares MT. Integration of molecular testing for the personalized management of patients with diffuse large B-cell lymphoma and follicular lymphoma. World J Clin Oncol 2023; 14:160-170. [PMID: 37124135 PMCID: PMC10134203 DOI: 10.5306/wjco.v14.i4.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/24/2023] [Accepted: 04/04/2023] [Indexed: 04/21/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%–40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.
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Affiliation(s)
- Ruth Stuckey
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Hugo Luzardo Henríquez
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | | | - José Carlos Rivero Vera
- Department of Anatomical Pathology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Cristina Bilbao-Sieyro
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Department of Morphology, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
| | - María Teresa Gómez-Casares
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Medical Science, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
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22
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Fan S, Wang T, You F, Zhang T, Li Y, Ji C, Han Z, Sheng B, Zhai X, An G, Meng H, Yang L. B7-H3 chimeric antigen receptor-modified T cell shows potential for targeted treatment of acute myeloid leukaemia. Eur J Med Res 2023; 28:129. [PMID: 36941687 PMCID: PMC10026503 DOI: 10.1186/s40001-023-01049-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 02/07/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND AND AIMS Chimeric antigen receptor (CAR)-T cell therapy is a novel type of immunotherapy. However, the use of CAR-T cells to treat acute myeloid leukaemia (AML) has limitations. B7-H3 is expressed in several malignancies, including some types of AML cells. However, its expression in normal tissues is low. Therefore, B7-H3 is ideal for targeted AML therapy. MATERIALS AND METHODS First, we constructed B7-H3 CAR that can target B7-H3, and then constructed B7-H3-CAR-T cells in vitro, which were co-incubated with six AML cell lines expressing different levels of B7-H3, respectively. The toxicity and cytokines were detected by flow cytometry. In vivo, AML model was established in B-NSG mice to study the toxicity of B7-H3-CAR T on AML cells. RESULTS In vitro functional tests showed that B7-H3-CAR-T cells were cytotoxic to B7-H3-positive AML tumor cells and had good scavenging effect on B7-H3-expressing AML cell lines, and the cytokine results were consistent. In vivo, B7-H3-CAR-T cells significantly inhibited tumor cell growth in a mouse model of AML, prolonging mouse survival compared with controls. CONCLUSION B7-H3-CAR-T cells may serve as a novel therapeutic method for the targeted treatment of AML.
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Affiliation(s)
- Shuangshuang Fan
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Tian Wang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, China
| | - Fengtao You
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China
| | - Tingting Zhang
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yafen Li
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China
| | - Cheng Ji
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Zhichao Han
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Binjie Sheng
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Xiaochen Zhai
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Gangli An
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China
| | - Huimin Meng
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China.
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China.
| | - Lin Yang
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China.
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China.
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, China.
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.
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23
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Gulden G, Sert B, Teymur T, Ay Y, Tiryaki NN, Mishra AK, Ovali E, Tarhan N, Tastan C. CAR-T Cells with Phytohemagglutinin (PHA) Provide Anti-Cancer Capacity with Better Proliferation, Rejuvenated Effector Memory, and Reduced Exhausted T Cell Frequencies. Vaccines (Basel) 2023; 11:vaccines11020313. [PMID: 36851194 PMCID: PMC9962293 DOI: 10.3390/vaccines11020313] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
The development of genetic modification techniques has led to a new era in cancer treatments that have been limited to conventional treatments such as chemotherapy. intensive efforts are being performed to develop cancer-targeted therapies to avoid the elimination of non-cancerous cells. One of the most promising approaches is genetically modified CAR-T cell therapy. The high central memory T cell (Tcm) and stem cell-like memory T cell (Tscm) ratios in the CAR-T cell population increase the effectiveness of immunotherapy. Therefore, it is important to increase the populations of CAR-expressing Tcm and Tscm cells to ensure that CAR-T cells remain long-term and have cytotoxic (anti-tumor) efficacy. In this study, we aimed to improve CAR-T cell therapy's time-dependent efficacy and stability, increasing the survival time and reducing the probability of cancer cell growth. To increase the sub-population of Tcm and Tscm in CAR-T cells, we investigated the production of a long-term stable and efficient cytotoxic CAR-T cell by modifications in the cell activation-dependent production using Phytohemagglutinin (PHA). PHA, a lectin that binds to the membranes of T cells and increases metabolic activity and cell division, is studied to increase the Tcm and Tscm population. Although it is known that PHA significantly increases Tcm cells, B-lymphocyte antigen CD19-specific CAR-T cell expansion, its anti-cancer and memory capacity has not yet been tested compared with aCD3/aCD28-amplified CAR-T cells. Two different types of CARs (aCD19 scFv CD8-(CD28 or 4-1BB)-CD3z-EGFRt)-expressing T cells were generated and their immunogenic phenotype, exhausted phenotype, Tcm-Tscm populations, and cytotoxic activities were determined in this study. The proportion of T cell memory phenotype in the CAR-T cell populations generated by PHA was observed to be higher than that of aCD3/aCD28-amplified CAR-T cells with similar and higher proliferation capacity. Here, we show that PHA provides long-term and efficient CAR-T cell production, suggesting a potential alternative to aCD3/aCD28-amplified CAR-T cells.
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Affiliation(s)
- Gamze Gulden
- Molecular Biology, Institute of Science and Technology, Üsküdar University, Istanbul 34662, Turkey
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
| | - Berranur Sert
- Molecular Biology, Institute of Science and Technology, Üsküdar University, Istanbul 34662, Turkey
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
| | - Tarik Teymur
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
- Molecular Biology and Genetics Department, Faculty of Engineering and Natural Science, Üsküdar University, Istanbul 34662, Turkey
| | - Yasin Ay
- Molecular Biology, Institute of Science and Technology, Üsküdar University, Istanbul 34662, Turkey
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
| | - Nulifer Neslihan Tiryaki
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
- Molecular Biology and Genetics Department, Faculty of Engineering and Natural Science, Üsküdar University, Istanbul 34662, Turkey
| | - Abhinava K. Mishra
- Molecular, Cellular and Developmental Biology Department, University of California Santa Barbara, Santa Barbara, CA 93106, USA
| | - Ercument Ovali
- Acıbadem Labcell Cellular Therapy Laboratory, Istanbul 34752, Turkey
| | - Nevzat Tarhan
- Faculty of Humanities and Social Sciences, Üsküdar University, Istanbul 34662, Turkey
| | - Cihan Tastan
- Transgenic Cell Technologies and Epigenetic Application and Research Center (TRGENMER), Üsküdar University, Istanbul 34662, Turkey
- Molecular Biology and Genetics Department, Faculty of Engineering and Natural Science, Üsküdar University, Istanbul 34662, Turkey
- Correspondence:
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24
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Marinos A, Heslop HE. Should all CAR-T therapy for acute lymphoblastic leukemia Be consolidated with allogeneic stem cell transplant? Best Pract Res Clin Haematol 2022; 35:101414. [PMID: 36517124 PMCID: PMC10683866 DOI: 10.1016/j.beha.2022.101414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Autologous T cells genetically modified with a CD19 chimeric antigen receptor are an effective therapy for children and adults with relapsed or refractory acute lymphoblastic leukemia with initial response rates ranging from 70 to 85%. Unfortunately, about half of these responding patients will subsequently relapse raising the question of whether allogeneic hemopoietic stem cell transplant should be considered as a consolidative therapy. Currently efforts are focused on defining risk factors for relapse to try and develop algorithms predicting which patients may benefit from allogenic transplant.
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Affiliation(s)
- Alejandro Marinos
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA
| | - Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA.
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25
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Goldsmith SR, Ghobadi A, Dipersio JF, Hill B, Shadman M, Jain T. Chimeric Antigen Receptor T Cell Therapy versus Hematopoietic Stem Cell Transplantation: An Evolving Perspective. Transplant Cell Ther 2022; 28:727-736. [PMID: 35878743 PMCID: PMC10487280 DOI: 10.1016/j.jtct.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/30/2022] [Accepted: 07/16/2022] [Indexed: 11/27/2022]
Abstract
Cellular therapy modalities, including autologous (auto-) hematopoietic cell transplantation (HCT), allogeneic (allo-) HCT, and now chimeric antigen receptor (CAR) T cell therapy, have demonstrated long-term remission in advanced hematologic malignancies. Auto-HCT and allo-HCT, through hematopoietic rescue, have permitted the use of higher doses of chemotherapy. Allo-HCT also introduced a nonspecific immune-mediated targeting of malignancy resulting in protection from relapse, although at the expense of similar targeting of normal host cells. In contrast, CAR T therapy, through genetically engineered immunotherapeutic precision, allows for redirection of autologous immune effector cells against malignancy in an antigen-specific and MHC-independent fashion, with demonstrated efficacy in patients who are refractory to cytotoxic chemotherapy. It too has unique toxicities and challenges, however. Non-Hodgkin lymphoma (including large B cell lymphoma, mantle cell lymphoma, and follicular lymphoma), B cell acute lymphoblastic leukemia, and multiple myeloma are the 3 main diseases associated with the use of fully developed CAR T products with widespread deployment. Recent and ongoing clinical trials have been examining the interface among the 3 cellular therapy modalities (auto-HCT, allo-HCT, and CAR T) to determine whether they should be "complementary" or "competitive" therapies. In this review, we examine the current state of this interface with respect to the most recent data and delve into the controversies and conclusions that may inform clinical decision making.
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Affiliation(s)
- Scott R Goldsmith
- Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, California; Division of Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri.
| | - Armin Ghobadi
- Division of Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - John F Dipersio
- Division of Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Brian Hill
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Mayzar Shadman
- Clinical Research Division, Fred Hutch Cancer Center and Medical Oncology division, University of Washington, Seattle, Washington
| | - Tania Jain
- Division of Hematological Malignancies and Bone Marrow Transplantation, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
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Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol 2022; 29:6864-6892. [PMID: 36290818 PMCID: PMC9600738 DOI: 10.3390/curroncol29100541] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 01/13/2023] Open
Abstract
Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Dipanjan Debnath
- Department of Internal Medicine, Medstar Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA
| | - Marion L. Hartley
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Marcus S. Noel
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
- Correspondence:
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27
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Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113545. [PMID: 35684481 PMCID: PMC9182385 DOI: 10.3390/molecules27113545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.
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28
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Bôle-Richard E, Pemmaraju N, Caël B, Daguindau E, Lane AA. CD123 and More: How to Target the Cell Surface of Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancers (Basel) 2022; 14:2287. [PMID: 35565416 PMCID: PMC9099711 DOI: 10.3390/cancers14092287] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia derived from plasmacytoid dendritic cells (pDCs). It is associated with a remarkably poor prognosis and unmet need for better therapies. Recently, the first-in-class CD123-targeting therapy, tagraxofusp, was approved for treatment of BPDCN. Other CD123-targeting strategies are in development, including bispecific antibodies and combination approaches with tagraxofusp and other novel agents. In other blood cancers, adoptive T-cell therapy using chimeric antigen receptor (CAR)-modified T cells represents a promising new avenue in immunotherapy, showing durable remissions in some relapsed hematologic malignancies. Here, we report on novel and innovative therapies in development to target surface molecules in BPDCN currently in clinical trials or in preclinical stages. We also discuss new cell surface targets that may have implications for future BPDCN treatment.
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Affiliation(s)
- Elodie Bôle-Richard
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besancon, France; (B.C.); (E.D.)
| | - Naveen Pemmaraju
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Blandine Caël
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besancon, France; (B.C.); (E.D.)
| | - Etienne Daguindau
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besancon, France; (B.C.); (E.D.)
- Service Hématologie, CHU Besançon, F-25000 Besancon, France
| | - Andrew A. Lane
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
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Mardi A, Shirokova AV, Mohammed RN, Keshavarz A, Zekiy AO, Thangavelu L, Mohamad TAM, Marofi F, Shomali N, Zamani A, Akbari M. Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction. Cancer Cell Int 2022; 22:168. [PMID: 35488303 PMCID: PMC9052538 DOI: 10.1186/s12935-022-02585-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a promising and rapidly expanding therapeutic option for a wide range of human malignancies. Despite the ongoing progress of CAR T-cell therapy in hematologic malignancies, the application of this therapeutic strategy in solid tumors has encountered several challenges due to antigen heterogeneity, suboptimal CAR T-cell trafficking, and the immunosuppressive features of the tumor microenvironment (TME). Oncolytic virotherapy is a novel cancer therapy that employs competent or genetically modified oncolytic viruses (OVs) to preferentially proliferate in tumor cells. OVs in combination with CAR T-cells are promising candidates for overcoming the current drawbacks of CAR T-cell application in tumors through triggering immunogenic cell death (ICD) in cancer cells. ICD is a type of cellular death in which danger-associated molecular patterns (DAMPs) and tumor-specific antigens are released, leading to the stimulation of potent anti-cancer immunity. In the present review, we discuss the biological causes of ICD, different types of ICD, and the synergistic combination of OVs and CAR T-cells to reach potent tumor-specific immunity.
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Affiliation(s)
- Amirhossein Mardi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anastasia V Shirokova
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Science, Cihan University of Sulaimaniya, Suleimanyah, Kurdistan region, Iraq.,College of. Veterinary Medicine, University of Sulaimani, Suleimanyah, Iraq
| | - Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Talar Ahmad Merza Mohamad
- Department of Pharmacology and Toxicology, Clinical Pharmacy, Hawler Medical University, College of Pharmacy, Kurdistan Region-Erbil, Iraq
| | - Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Dholakia J, Cohen AC, Leath CA, Evans ET, Alvarez RD, Thaker PH. Development of Delivery Systems for Local Administration of Cytokines/Cytokine Gene-Directed Therapeutics: Modern Oncologic Implications. Curr Oncol Rep 2022; 24:389-397. [PMID: 35141857 PMCID: PMC10466172 DOI: 10.1007/s11912-022-01221-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW In this review, we discuss modern cytokine delivery systems in oncologic care, focusing on modalities being developed in the clinical trials or currently in use. These include pegylation, immune-cytokine drug conjugates, cytokine-expressing plasmid nanoparticles, nonviral cytokine nanoparticles, viral systems, and AcTakines. RECENT FINDINGS Cytokine therapy has the potential to contribute to cancer treatment options by modulating the immune system towards an improved antitumor response and has shown promise both independently and in combination with other immunotherapy agents. Despite promising preliminary studies, systemic toxicities and challenges with administration have limited the impact of unmodified cytokine therapy. In the last decade, novel delivery systems have been developed to address these challenges and facilitate cytokine-based oncologic treatments. Novel delivery systems provide potential solutions to decrease dose-limiting side effects, facilitate administration, and increase the therapeutic activity of cytokine treatments in oncology care. The expanding clinical and translational research in these systems provides an opportunity to augment the armamentarium of immune oncology and may represent the next frontier of cytokine-based immuno-oncology.
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Affiliation(s)
- Jhalak Dholakia
- Department of Obstetrics & Gynecology, University of Alabama Division of Gynecologic Oncology, 1700 6th Avenue South, Room 10250, Birmingham, AL, 35249-7333, USA.
| | - Alexander C Cohen
- Department of Obstetrics & Gynecology, Washington University in St. Louis Division of Gynecologic Oncology, St. Louis, MO, USA
| | - Charles A Leath
- Department of Obstetrics & Gynecology, University of Alabama Division of Gynecologic Oncology, 1700 6th Avenue South, Room 10250, Birmingham, AL, 35249-7333, USA
| | - Elizabeth T Evans
- Department of Obstetrics & Gynecology, University of Alabama Division of Gynecologic Oncology, 1700 6th Avenue South, Room 10250, Birmingham, AL, 35249-7333, USA
| | - Ronald D Alvarez
- Department of Obstetrics & Gynecology, Vanderbilt University Division of Gynecologic Oncology, Nashville, TN, USA
| | - Premal H Thaker
- Department of Obstetrics & Gynecology, Washington University in St. Louis Division of Gynecologic Oncology, St. Louis, MO, USA
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Stock S, Kluever AK, Endres S, Kobold S. Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners. Biomedicines 2022; 10:biomedicines10020307. [PMID: 35203517 PMCID: PMC8869718 DOI: 10.3390/biomedicines10020307] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 11/16/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable response rates and revolutionized the treatment of patients suffering from defined hematological malignancies. However, many patients still do not respond to this therapy or relapse after an initial remission, underscoring the need for improved efficacy. Insufficient in vivo activity, persistence, trafficking, and tumor infiltration of CAR T cells, as well as antigen escape and treatment-associated adverse events, limit the therapeutic success. Multiple strategies and approaches have been investigated to further improve CAR T cell therapy. Besides genetic modification of the CAR itself, the combination with other treatment modalities has the potential to improve this approach. In particular, combining CAR T cells with clinically approved compounds such as monoclonal antibodies and small molecule inhibitors might be a promising strategy. Combination partners could already be applied during the production process to influence the cellular composition and immunophenotype of the final CAR T cell product. Alternatively, simultaneous administration of clinically approved compounds with CAR T cells would be another feasible avenue. In this review, we will discuss current strategies to combine CAR T cells with compounds to overcome recent limitations and further enhance this promising cancer therapy, potentially broadening its application beyond hematology.
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Affiliation(s)
- Sophia Stock
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, 80337 Munich, Germany; (A.-K.K.); (S.E.)
- Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) of Munich, 81337 Munich, Germany
- Correspondence: (S.S.); (S.K.)
| | - Anna-Kristina Kluever
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, 80337 Munich, Germany; (A.-K.K.); (S.E.)
| | - Stefan Endres
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, 80337 Munich, Germany; (A.-K.K.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80336 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, 80337 Munich, Germany; (A.-K.K.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80336 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
- Correspondence: (S.S.); (S.K.)
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Radic M, Neeli I, Marion T. Prospects for CAR T cell immunotherapy in autoimmune diseases: clues from Lupus. Expert Opin Biol Ther 2022; 22:499-507. [PMID: 35089116 DOI: 10.1080/14712598.2022.2026921] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Medicine stands at the threshold of a new era heralded by the vast potential of cell engineering. Like advances made possible by genetic engineering, current prospects for purposeful control of cell functions through cell engineering may bring breakthroughs in the treatment of previously intractable diseases. AREAS COVERED Engineering of cytotoxic T cells for expression of chimeric antigen receptors (CARs) instructs them to attack and destroy malignant cells and thus provides an exciting new approach in oncology. A decade of practical experience and first-in-human trials encourage the search for new and broader uses of CAR technology, including in autoimmune diseases. EXPERT OPINION Systemic lupus erythematosus is an example of a broader category of autoimmune diseases, for which cell engineering will provide a powerful new therapeutic approach. This article describes different types of CAR T cell strategies that will provide new treatment options for patients with autoimmune diseases and replace conventional therapies.
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Affiliation(s)
- Marko Radic
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN (USA)
| | - Indira Neeli
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN (USA)
| | - Tony Marion
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN (USA)
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Zhang W, Gaikwad H, Groman EV, Purev E, Simberg D, Wang G. Highly aminated iron oxide nanoworms for simultaneous manufacturing and labeling of chimeric antigen receptor T cells. JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS 2022; 541:168480. [PMID: 34720339 PMCID: PMC8553019 DOI: 10.1016/j.jmmm.2021.168480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Cell based therapies including chimeric antigen receptor (CAR) T cells are promising for treating leukemias and solid cancers. At the same time, there is interest in enhancing the functionality of these cells via surface decoration with nanoparticles (backpacking). Magnetic nanoparticle cell labeling is of particular interest due to opportunities for magnetic separation, in vivo manipulation, drug delivery and magnetic resonance imaging (MRI). While modification of T cells with magnetic nanoparticles (MNPs) was explored before, we questioned whether MNPs are compatible with CAR-T cells when introduced during the manufacturing process. We chose highly aminated 120 nm crosslinked iron oxide nanoworms (CLIO NWs, ~36,000 amines per NW) that could efficiently label different adherent cell lines and we used CD123 CAR-T cells as the labeling model. The CD123 CAR-T cells were produced in the presence of CLIO NWs, CLIO NWs plus protamine sulfate (PS), or PS only. The transduction efficiency of lentiviral CD123 CAR with only NWs was ~23% lower than NW+PS and PS groups (~33% and 35%, respectively). The cell viability from these three transduction conditions was not reduced within CAR-T cell groups, though lower compared to non-transduced T cells (mock T). Use of CLIO NWs instead of, or together with cationic protamine sulfate for enhancement of lentiviral transduction resulted in comparable levels of CAR expression and viability but decreased the proportion of CD8+ cells and increased the proportion of CD4+ cells. CD123 CAR-T transduced in the presence of CLIO NWs, CLIO NWs plus PS, or PS only, showed similar level of cytotoxicity against leukemic cell lines. Furthermore, fluorescence microscopy imaging demonstrated that CD123 CAR-T cells labeled with CLIO NW formed rosettes with CD123+ leukemic cells as the non-labeled CAR-T cells, indicating that the CAR-T targeting to tumor cells has maintained after CLIO NW labeling. The in vivo trafficking of the NW labeled CAR-T cells showed the accumulation of CAR-T labeled with NWs primarily in the bone marrow and spleen. CAR-T cells can be magnetically labeled during their production while maintaining functionality using the positively charged iron oxide NWs, which enable the in vivo biodistribution and tracking of CAR-T cells.
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Affiliation(s)
- Wei Zhang
- Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Hanmant Gaikwad
- Translational Bio-Nanosciences Laboratory, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Ernest V. Groman
- Translational Bio-Nanosciences Laboratory, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Enkhtsetseg Purev
- Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Dmitri Simberg
- Translational Bio-Nanosciences Laboratory, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Corresponding Authors: (Dmitri Simberg), (Guankui Wang)
| | - Guankui Wang
- Translational Bio-Nanosciences Laboratory, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Corresponding Authors: (Dmitri Simberg), (Guankui Wang)
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Duan Y, Chen R, Huang Y, Meng X, Chen J, Liao C, Tang Y, Zhou C, Gao X, Sun J. Tuning the ignition of CAR: optimizing the affinity of scFv to improve CAR-T therapy. Cell Mol Life Sci 2021; 79:14. [PMID: 34966954 PMCID: PMC11073403 DOI: 10.1007/s00018-021-04089-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 10/19/2022]
Abstract
How single-chain variable fragments (scFvs) affect the functions of chimeric antigen receptors (CARs) has not been well studied. Here, the components of CAR with an emphasis on scFv were described, and then several methods to measure scFv affinity were discussed. Next, scFv optimization studies for CD19, CD38, HER2, GD2 or EGFR were overviewed, showing that tuning the affinity of scFv could alleviate the on-target/off-tumor toxicity. The affinities of scFvs for different antigens were also summarized to designate a relatively optimal working range for CAR design. Last, a synthetic biology approach utilizing a low-affinity synthetic Notch (synNotch) receptor to achieve ultrasensitivity of antigen-density discrimination and murine models to assay the on-target/off-tumor toxicity of CARs were highlighted. Thus, this review provides preliminary guidelines of choosing the right scFvs for CARs.
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Affiliation(s)
- Yanting Duan
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Ruoqi Chen
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Yanjie Huang
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Xianhui Meng
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Jiangqing Chen
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Chan Liao
- Department of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yongmin Tang
- Department of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chun Zhou
- School of Public Health, and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiaofei Gao
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Jie Sun
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China.
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Sutra Del Galy A, Menegatti S, Fuentealba J, Lucibello F, Perrin L, Helft J, Darbois A, Saitakis M, Tosello J, Rookhuizen D, Deloger M, Gestraud P, Socié G, Amigorena S, Lantz O, Menger L. In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4 + T H1 cell response. Sci Immunol 2021; 6:eabe8219. [PMID: 34860579 DOI: 10.1126/sciimmunol.abe8219] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
[Figure: see text].
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Affiliation(s)
| | - Silvia Menegatti
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Jaime Fuentealba
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | | | - Laetitia Perrin
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Julie Helft
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Aurélie Darbois
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Michael Saitakis
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Jimena Tosello
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Derek Rookhuizen
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
| | - Marc Deloger
- INSERM US23, CNRS UMS 3655, Gustave Roussy Cancer Campus, 94800 Villejuif, France
| | - Pierre Gestraud
- Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, MINES ParisTech, INSERM U900, Paris 75005, France
| | - Gérard Socié
- AP-HP Hospital Saint Louis, Hematology/Transplantation, Paris 75010, France
| | | | - Olivier Lantz
- INSERM U932, PSL University, Institut Curie, Paris 75005, France.,Laboratoire d'immunologie clinique, Institut Curie, Paris 75005, France.,Centre d'investigation Clinique en Biothérapie Gustave-Roussy Institut Curie (CIC-BT1428), Institut Curie, Paris 75005, France
| | - Laurie Menger
- INSERM U932, PSL University, Institut Curie, Paris 75005, France
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Knopick P, Terman D, Riha N, Alvine T, Larson R, Badiou C, Lina G, Ballantyne J, Bradley D. Endogenous HLA-DQ8αβ programs superantigens (SEG/SEI) to silence toxicity and unleash a tumoricidal network with long-term melanoma survival. J Immunother Cancer 2021; 8:jitc-2020-001493. [PMID: 33109631 PMCID: PMC7592263 DOI: 10.1136/jitc-2020-001493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2020] [Indexed: 12/17/2022] Open
Abstract
Background As the most powerful T cell agonists known, superantigens (SAgs) have enormous potential for cancer immunotherapy. Their development has languished due to high incidence (60%–80%) of seroreactive neutralizing antibodies in humans and tumor necrosis factor-α (TNFα)-mediated cardiopulmonary toxicity. Such toxicity has narrowed their therapeutic index while neutralizing antibodies have nullified their therapeutic effects. Methods Female HLA-DQ8 (DQA*0301/DQB*0302) tg mice expressing the human major histocompatibility complex II (MHCII) HLA-DQ8 allele on a high proportion of PBL, spleen and lymph node cells were used. In the established tumor model, staphylococcal enterotoxin G and staphylococcal enterotoxin I (SEG/ SEI) (50 µg each) were injected on days 6 and 9 following tumor inoculation. Lymphoid, myeloid cells and tumor cell digests from tumor tissue were assayed using flow cytometry or quantitated using a cytometric bead array. Tumor density, necrotic and viable areas were quantitated using the ImageJ software. Results In a discovery-driven effort to address these problems we introduce a heretofore unrecognized binary complex comprizing SEG/SEI SAgs linked to the endogenous human MHCII HLA-DQ8 allele in humanized mice. By contrast to staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin B (SEB) deployed previously in clinical trials, SEG and SEI does not exhibit neutralizing antibodies in humans or TNFα-mediated toxicity in humanized HLA-DQ8 mice. In the latter model wherein SAg behavior is known to be ‘human-like’, SEG/SEI induced a powerful tumoricidal response and long-term survival against established melanoma in 82% of mice. Other SAgs deployed in the same model displayed toxic shock. Initially, HLA-DQ8 mediated melanoma antigen priming, after which SEG/SEI unleashed a broad CD4+ and CD8+ antitumor network marked by expansion of melanoma reactive T cells and interferon-γ (IFNy) in the tumor microenvironment (TME). SEG/SEI further initiated chemotactic recruitment of tumor reactive T cells to the TME converting the tumor from ‘cold’ to a ‘hot’. Long-term survivors displayed remarkable resistance to parental tumor rechallenge along with the appearance of tumor specific memory and tumor reactive T memory cells. Conclusions Collectively, these findings show for the first time that the SEG/SEI-(HLA-DQ8) empowers priming, expansion and recruitment of a population of tumor reactive T cells culminating in tumor specific memory and long-term survival devoid of toxicity. These properties distinguish SEG/SEI from other SAgs used previously in human tumor immunotherapy. Consolidation of these principles within the SEG/SEI-(HLA-DQ8) complex constitutes a conceptually new therapeutic weapon with compelling translational potential.
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Affiliation(s)
- Peter Knopick
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - David Terman
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Nathan Riha
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Travis Alvine
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Riley Larson
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Cedric Badiou
- University of Lyon, Lyon, Auvergne-Rhône-Alpes, France
| | - Gerard Lina
- University of Lyon 1 University Institute of Tecnology Lyon 1, Villeurbanne, Auvergne-Rhône-Alpes, France
| | | | - David Bradley
- Biomedical Sciences, Universtiy of North Dakota School of Medicine, Grand Forks, North Dakota, USA
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Yoo HJ, Harapan BN. Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology. Immunol Res 2021; 69:471-486. [PMID: 34554405 PMCID: PMC8580929 DOI: 10.1007/s12026-021-09236-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022]
Abstract
With recent advances, chimeric antigen receptor (CAR) immunotherapy has become a promising modality for patients with refractory cancer diseases. The successful results of CAR T cell therapy in relapsed and refractory B-cell malignancies shifted the paradigm of cancer immunotherapy by awakening the scientific, clinical, and commercial interest in translating this technology for the treatment of solid cancers. This review elaborates on fundamental principles of CAR T cell therapy (development of CAR construct, challenges of CAR T cell therapy) and its application on solid tumors as well as CAR T cell therapy potential in the field of neuro-oncology. Glioblastoma (GBM) is identified as one of the most challenging solid tumors with a permissive immunological milieu and dismal prognosis. Standard multimodal treatment using maximal safe resection, radiochemotherapy, and maintenance chemotherapy extends the overall survival beyond a year. Recurrence is, however, inevitable. GBM holds several unique features including its vast intratumoral heterogeneity, immunosuppressive environment, and a partially permissive anatomic blood–brain barrier, which offers a unique opportunity to investigate new treatment approaches. Tremendous efforts have been made in recent years to investigate novel CAR targets and target combinations with standard modalities for solid tumors and GBM to improve treatment efficacy. In this review, we outline the history of CAR immunotherapy development, relevant CAR target antigens validated with CAR T cells as well as preclinical approaches in combination with adjunct approaches via checkpoint inhibition, bispecific antibodies, and second-line systemic therapies that enhance anticancer efficacy of the CAR-based cancer immunotherapy.
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Affiliation(s)
- Hyeon Joo Yoo
- Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Biyan Nathanael Harapan
- Department of Neurosurgery, University Hospital, Ludwig-Maximilians-University of Munich, 81377, Munich, Germany.
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Zhang M, Zhao Z, Pritykin Y, Hannum M, Scott AC, Kuo F, Sanghvi V, Chan TA, Seshan V, Wendel HG, Schietinger A, Sadelain M, Huse M. Ectopic activation of the miR-200c-EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy. Sci Transl Med 2021; 13:eabg4328. [PMID: 34524864 PMCID: PMC9374309 DOI: 10.1126/scitranslmed.abg4328] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam, was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c–EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.
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Affiliation(s)
- Minggang Zhang
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Zeguo Zhao
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Yuri Pritykin
- Lewis-Sigler Institute for Integrative Genomics and Computer Science Department, Princeton University, Princeton, NJ 08540, USA
| | - Margaret Hannum
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Andrew C Scott
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Fengshen Kuo
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Viraj Sanghvi
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Timothy A Chan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Venkatraman Seshan
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Hans-Guido Wendel
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Andrea Schietinger
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michel Sadelain
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Morgan Huse
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Muthineni S, Zink K, Kambhampati S. A Primer on Chimera Associated Receptor T-Cells. MISSOURI MEDICINE 2021; 118:460-465. [PMID: 34658441 PMCID: PMC8504496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cancer continues to be one of the leading causes of death. Although survival rates have improved with current treatments for hematological malignancies, relapsed and refractory cases have poor prognosis. Immunotherapy against cancer cells offer new hope for curative response in these patients. Of those, Chimeric Antigen Receptor (CAR) T-cells are emerging as promising therapy for hematological malignancies, where T-lymphocytes are genetically engineered with CAR to recognize and eliminate specific tumor cells. The efficacy of CAR T-cell therapy is also being studied in solid tumors. In this review, the basic principles of CAR T-cell therapy are discussed.
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Affiliation(s)
- Sumalatha Muthineni
- Internal Medicine, Hematology/Oncology, practice at the Sarah Cannon Transplant and Cellular Therapy Program, Research Medical Center, Kansas City, Missouri
| | - Katelyn Zink
- Hematology/Oncology, practice at the Sarah Cannon Transplant and Cellular Therapy Program, Research Medical Center, Kansas City, Missouri
| | - Suman Kambhampati
- Hematology/Oncology, practice at the Sarah Cannon Transplant and Cellular Therapy Program, Research Medical Center, Kansas City, Missouri
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40
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Yeo D, Castelletti L, van Zandwijk N, Rasko JEJ. Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma. Cancers (Basel) 2021; 13:3932. [PMID: 34439085 PMCID: PMC8391149 DOI: 10.3390/cancers13163932] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/16/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Laura Castelletti
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Concord Repatriation General Hospital, Sydney Local Health District (SLHD), Concord, NSW 2139, Australia
| | - John E. J. Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
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Globerson Levin A, Rivière I, Eshhar Z, Sadelain M. CAR T cells: Building on the CD19 paradigm. Eur J Immunol 2021; 51:2151-2163. [PMID: 34196410 DOI: 10.1002/eji.202049064] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022]
Abstract
Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B- cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence-associated pathologies.
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Affiliation(s)
| | - Isabelle Rivière
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zelig Eshhar
- Immunology Lab, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Michel Sadelain
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Marofi F, Rahman HS, Achmad MH, Sergeevna KN, Suksatan W, Abdelbasset WK, Mikhailova MV, Shomali N, Yazdanifar M, Hassanzadeh A, Ahmadi M, Motavalli R, Pathak Y, Izadi S, Jarahian M. A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions. Front Immunol 2021; 12:681984. [PMID: 34248965 PMCID: PMC8261235 DOI: 10.3389/fimmu.2021.681984] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.
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Affiliation(s)
- Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Iraq
| | - Muhammad Harun Achmad
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - Klunko Nataliya Sergeevna
- Department of Economics and Industrial Engineering, St. Petersburg University of Management and Economics, St. Petersburg, Russia
- Department of Postgraduate and Doctoral Studies, Russian New University, Moscow, Russia
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Ali Hassanzadeh
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yashwant Pathak
- Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Department of Pharmaceutical Science, Faculty of Pharmacy, Airlangga University, Subaraya, Indonesia
| | - Sepideh Izadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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Martínez-Rubio Á, Chulián S, Blázquez Goñi C, Ramírez Orellana M, Pérez Martínez A, Navarro-Zapata A, Ferreras C, Pérez-García VM, Rosa M. A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia. Int J Mol Sci 2021; 22:6371. [PMID: 34198713 PMCID: PMC8232108 DOI: 10.3390/ijms22126371] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 01/02/2023] Open
Abstract
Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients' experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.
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Affiliation(s)
- Álvaro Martínez-Rubio
- Department of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain; (S.C.); (M.R.)
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain;
| | - Salvador Chulián
- Department of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain; (S.C.); (M.R.)
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain;
| | - Cristina Blázquez Goñi
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain;
- Department of Pediatric Hematology and Oncology, Hospital de Jerez, 11407 Cádiz, Spain
| | - Manuel Ramírez Orellana
- Department of Paediatric Haematology and Oncology, Instituto Investigación Sanitaria La Princesa, Hospital Infantil Universitario Niño Jesús, 28006 Madrid, Spain;
| | - Antonio Pérez Martínez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain; (A.P.M.); (A.N.-Z.); (C.F.)
- Pediatric Hemato-Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Alfonso Navarro-Zapata
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain; (A.P.M.); (A.N.-Z.); (C.F.)
| | - Cristina Ferreras
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain; (A.P.M.); (A.N.-Z.); (C.F.)
| | - Victor M. Pérez-García
- Mathematical Oncology Laboratory (MOLAB), Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, 13005 Ciudad Real, Spain;
- Departamento de Matemáticas, Escuela Técnica Superior de Ingenieros Industriales, Universidad de Castilla-La Mancha, 13005 Ciudad Real, Spain
| | - María Rosa
- Department of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain; (S.C.); (M.R.)
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain;
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Maulana TI, Kromidas E, Wallstabe L, Cipriano M, Alb M, Zaupa C, Hudecek M, Fogal B, Loskill P. Immunocompetent cancer-on-chip models to assess immuno-oncology therapy. Adv Drug Deliv Rev 2021; 173:281-305. [PMID: 33798643 DOI: 10.1016/j.addr.2021.03.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/08/2021] [Accepted: 03/17/2021] [Indexed: 12/12/2022]
Abstract
The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines.
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Vercellino L, de Jong D, di Blasi R, Kanoun S, Reshef R, Schwartz LH, Dercle L. Current and Future Role of Medical Imaging in Guiding the Management of Patients With Relapsed and Refractory Non-Hodgkin Lymphoma Treated With CAR T-Cell Therapy. Front Oncol 2021; 11:664688. [PMID: 34123825 PMCID: PMC8195284 DOI: 10.3389/fonc.2021.664688] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/05/2021] [Indexed: 12/21/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cells are a novel immunotherapy available for patients with refractory/relapsed non-Hodgkin lymphoma. In this indication, clinical trials have demonstrated that CAR T-cells achieve high rates of response, complete response, and long-term response (up to 80%, 60%, and 40%, respectively). Nonetheless, the majority of patients ultimately relapsed. This review provides an overview about the current and future role of medical imaging in guiding the management of non-Hodgkin lymphoma patients treated with CAR T-cells. It discusses the value of predictive and prognostic biomarkers to better stratify the risk of relapse, and provide a patient-tailored therapeutic strategy. At baseline, high tumor volume (assessed on CT-scan or on [18F]-FDG PET/CT) is a prognostic factor associated with treatment failure. Response assessment has not been studied extensively yet. Available data suggests that current response assessment developed on CT-scan or on [18F]-FDG PET/CT for cytotoxic systemic therapies remains relevant to estimate lymphoma response to CAR T-cell therapy. Nonetheless, atypical patterns of response and progression have been observed and should be further analyzed. The potential advantages as well as limitations of artificial intelligence and radiomics as tools providing high throughput quantitative imaging features is described.
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Affiliation(s)
- Laetitia Vercellino
- Nuclear Medicine Department Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Dorine de Jong
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Roberta di Blasi
- Onco-Hematology Department Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Salim Kanoun
- Cancer Research Center of Toulouse (CRCT), Team 9, INSERM UMR 1037, Toulouse, France
| | - Ran Reshef
- Blood and Marrow Transplantation and Cell Therapy Program, Division of Hematology/Oncology and Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York City, NY, United States
| | - Lawrence H. Schwartz
- Department of Radiology, New York Presbyterian, Columbia University Irving Medical Center, New York City, NY, United States
| | - Laurent Dercle
- Department of Radiology, New York Presbyterian, Columbia University Irving Medical Center, New York City, NY, United States
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Shao F, Long Y, Ji H, Jiang D, Lei P, Lan X. Radionuclide-based molecular imaging allows CAR-T cellular visualization and therapeutic monitoring. Am J Cancer Res 2021; 11:6800-6817. [PMID: 34093854 PMCID: PMC8171102 DOI: 10.7150/thno.56989] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is a new and effective form of adoptive cell therapy that is rapidly entering the mainstream for the treatment of CD19-positive hematological cancers because of its impressive effect and durable responses. Huge challenges remain in achieving similar success in patients with solid tumors. The current methods of monitoring CAR-T, including morphological imaging (CT and MRI), blood tests, and biopsy, have limitations to assess whether CAR-T cells are homing to tumor sites and infiltrating into tumor bed, or to assess the survival, proliferation, and persistence of CAR-T cells in solid tumors associated with an immunosuppressive microenvironment. Radionuclide-based molecular imaging affords improved CAR-T cellular visualization and therapeutic monitoring through either a direct cellular radiolabeling approach or a reporter gene imaging strategy, and endogenous cell imaging is beneficial to reflect functional information and immune status of T cells. Focusing on the dynamic monitoring and precise assessment of CAR-T therapy, this review summarizes the current applications of radionuclide-based noninvasive imaging in CAR-T cells visualization and monitoring and presents current challenges and strategic choices.
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Alhakamy NA, Curiel DT, Berkland CJ. The era of gene therapy: From preclinical development to clinical application. Drug Discov Today 2021; 26:1602-1619. [PMID: 33781953 DOI: 10.1016/j.drudis.2021.03.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/09/2020] [Accepted: 03/21/2021] [Indexed: 12/16/2022]
Abstract
Three decades of promise have culminated in the development of gene therapies that can be applied to a broad range of human diseases. After a brief history, we provide an overview of gene therapy types and delivery methods, gene editing technologies, regulatory affairs, clinical trials, approved products, ongoing challenges, and future goals. Information on clinical trials of candidates and on approved products for gene therapy developed between 1988 and 2020 is systematically collated. To obtain this global information, we scanned and reviewed more than 46,000 records of clinical trials from 17 clinical trial database providers. The medical benefits of transformative gene therapies are gradually being accepted by payors, and a significant increase in the number of gene therapy clinical trials and approved gene therapy products has resulted.
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Affiliation(s)
- Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - David T Curiel
- Department of Radiation Oncology, School of Medicine, Washington University, St. Louis, MO 63108, USA
| | - Cory J Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA; Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66047, USA.
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48
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Mangal JL, Handlos JL, Esrafili A, Inamdar S, Mcmillian S, Wankhede M, Gottardi R, Acharya AP. Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies. Cancers (Basel) 2021; 13:1123. [PMID: 33807867 PMCID: PMC7962004 DOI: 10.3390/cancers13051123] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/23/2021] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells.
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Affiliation(s)
- Joslyn L. Mangal
- Biological Design Graduate Program, School for Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA;
| | - Jamie L. Handlos
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
| | - Arezoo Esrafili
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
| | - Sahil Inamdar
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
| | - Sidnee Mcmillian
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
| | - Mamta Wankhede
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
| | - Riccardo Gottardi
- Department of Pediatrics, Division of Pulmonary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Fondazione Ri.MED, 90133 Palermo, Italy
| | - Abhinav P. Acharya
- Biological Design Graduate Program, School for Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85281, USA;
- Department of Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA; (J.L.H.); (A.E.); (S.I.); (S.M.); (M.W.)
- Department of Materials Science and Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85281, USA
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Tempe, AZ 85281, USA
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Castelletti L, Yeo D, van Zandwijk N, Rasko JEJ. Anti-Mesothelin CAR T cell therapy for malignant mesothelioma. Biomark Res 2021; 9:11. [PMID: 33588928 PMCID: PMC7885509 DOI: 10.1186/s40364-021-00264-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/31/2021] [Indexed: 12/14/2022] Open
Abstract
Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.
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Affiliation(s)
- Laura Castelletti
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia.,Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.,Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, Australia
| | - Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia.,Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.,Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.,Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, Australia.,Concord Repatriation General Hospital, Sydney Local Health District (SLHD), Concord, Australia
| | - John E J Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, Australia. .,Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia. .,Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, Australia. .,Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, Australia.
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Integrative Expression and Prognosis Analysis of DHX37 in Human Cancers by Data Mining. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6576210. [PMID: 33490273 PMCID: PMC7801084 DOI: 10.1155/2021/6576210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/10/2020] [Accepted: 12/19/2020] [Indexed: 12/24/2022]
Abstract
DHEA-Box Helicase 37 (DHX37) is a putative RNA helicase. It is involved in various RNA secondary structure alteration processes, including translation, nuclear splicing, and ribosome assembly. It is reported to be associated with the neurodevelopmental disorder with brain anomalies, and a recent study suggests that DHX37 is a functional regulator of CD8 T cells. Dysregulation of the CD8 T cell function is closely related to defective antitumor immune responses. In the present study, we investigated the expression, mutation, and prognostic role of DHX37 in human cancers, mainly by mining publicly available datasets. Our results suggested that DHX37 was significantly upregulated in 17 kinds of tumors. Mutations including deletions, insertions, and substitutions of DHX37 were widely detected. Besides, the expression of DHX37 was negatively correlated with immune-related genes PD-L1, RGS16, and TOX, and it was positively associated with TIM3, LAG3, and NCOR2. Through biofunctional analysis, we observed that DHX37 was significantly enriched in cancer-related pathways such as cell cycle, DNA replication, mismatch repair, RNA degradation, and RNA polymerase. In conclusion, the study explored the significance of DHX37 in human cancers. DHX37 may serve as a potential target for cancer immunotherapy.
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