1
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Arabi S, Fadaee M, Kazemi T, Rahmani M. Advancements in colorectal cancer immunotherapy: from CAR-T cells to exosome-based therapies. J Drug Target 2025:1-12. [PMID: 39754507 DOI: 10.1080/1061186x.2024.2449482] [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: 09/27/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.
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Affiliation(s)
- Sepideh Arabi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Manouchehr Fadaee
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammadreza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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2
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Li H, Wang F, Zhao H, Cao J, Wang S, Li H, Savoldo B, Rao E, Dotti G, Du H. Preclinical assessment of the efficacy of B7-H3 CAR-T in renal cell carcinoma. Mol Immunol 2024; 176:1-10. [PMID: 39514948 PMCID: PMC11631664 DOI: 10.1016/j.molimm.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 10/20/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
B7-H3 is a type I transmembrane protein that belongs to the B7 immune checkpoint protein family, is aberrantly expressed in cancer cells, but rarely expressed in normal tissues, making it an attractive target for cancer therapy. Here, we found B7-H3 is highly expressed in the renal cell carcinoma (RCC) tumor tissues and RCC cell lines, but is undetectable in normal renal tissues. Therefore, we engineered second-generation CAR-T cells targeting B7-H3, incorporating either CD28 or 4-1BB co-stimulatory domains. Both CAR-T cell variants demonstrated potent antitumor activity against RCC tumors in vitro and in metastatic and orthotopic RCC mouse models. Furthermore, the B7-H3 CAR-T cells exhibited remarkable proliferation and robust cytokine release when co-cultured with RCC cancer cells. These findings demonstrated that targeting B7-H3 by CAR-T cells potentially offering a new treatment option for RCC patients.
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Affiliation(s)
- Huizhong Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Fei Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Haifang Zhao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Jiale Cao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Shiyuan Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Hongxia Li
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101125, China
| | - Barbara Savoldo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Enyu Rao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
| | - Hongwei Du
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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3
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Karimi-Googheri M, Gholipourmalekabadi M, Madjd Z, Shabani Z, Rostami Z, Kazemi Arababadi M, Kiani J. The mechanisms of B-cell acute lymphoblastic leukemia relapsing following chimeric antigen receptor-T cell therapy; the plausible future strategies. Mol Biol Rep 2024; 51:1135. [PMID: 39514017 DOI: 10.1007/s11033-024-10061-2] [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: 07/25/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Research has demonstrated the high mortality and morbidity associated with B-Acute lymphoblastic lymphoma (B-ALL). Researchers have developed several therapeutic approaches to combat the disorder. Recently, researchers developed chimeric antigen receptors (CARs)-T cells, which recognize antigens independently of major histocompatibility complexes (MHCs) and activate at a higher level with additional persistence. However, relapsing B-ALL has been reported in several cases. This review article was aimed to collecting recent information regarding the mechanisms used by B-ALL-related lymphocytes to escape from CAR-T cells and the plausible resolution projects.
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Affiliation(s)
- Masoud Karimi-Googheri
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mazaher Gholipourmalekabadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ziba Shabani
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zhila Rostami
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
- Departmant of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Jafar Kiani
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
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4
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Montagna E, de Campos NSP, Porto VA, da Silva GCP, Suarez ER. CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types. BMC Cancer 2024; 24:1037. [PMID: 39174908 PMCID: PMC11340198 DOI: 10.1186/s12885-024-12651-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/16/2024] [Indexed: 08/24/2024] Open
Abstract
CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.
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MESH Headings
- Humans
- Age Factors
- Antigens, CD19/immunology
- Immunotherapy, Adoptive/methods
- Leukemia, B-Cell/therapy
- Leukemia, B-Cell/immunology
- Leukemia, B-Cell/mortality
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/therapy
- Lymphoma, B-Cell/mortality
- Receptors, Antigen, T-Cell/immunology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/immunology
- Treatment Outcome
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Affiliation(s)
- Erik Montagna
- Centro Universitário FMABC, Santo André, 09060-870, SP, Brazil
| | - Najla Santos Pacheco de Campos
- Center for Natural and Human Sciences, Federal University of ABC, Santo Andre, 09210-580, SP, Brazil
- Graduate Program in Medicine - Hematology and Oncology, Federal University of São Paulo, São Paulo, 04023-062, SP, Brazil
| | - Victoria Alves Porto
- Center for Natural and Human Sciences, Federal University of ABC, Santo Andre, 09210-580, SP, Brazil
| | | | - Eloah Rabello Suarez
- Center for Natural and Human Sciences, Federal University of ABC, Santo Andre, 09210-580, SP, Brazil.
- Graduate Program in Medicine - Hematology and Oncology, Federal University of São Paulo, São Paulo, 04023-062, SP, Brazil.
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5
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Jing J, Ma Y, Xie Z, Wang B, Chen Y, Chi E, Wang J, Zhang K, Wang Z, Li S. Acute T-cell lymphoblastic leukemia: chimeric antigen receptor technology may offer a new hope. Front Immunol 2024; 15:1410519. [PMID: 39192970 PMCID: PMC11347323 DOI: 10.3389/fimmu.2024.1410519] [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: 04/01/2024] [Accepted: 07/15/2024] [Indexed: 08/29/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment.
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Affiliation(s)
- Jiajie Jing
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Yuan Ma
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Ziwen Xie
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Bingyan Wang
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Yueming Chen
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Enjie Chi
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Jiadong Wang
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Kejin Zhang
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
| | - Zhujun Wang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sisi Li
- Department of Clinical Medicine, Hangzhou City University School of Medicine, Hangzhou, China
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6
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Carrillo MA, Zhen A, Mu W, Rezek V, Martin H, Peterson CW, Kiem HP, Kitchen SG. Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells. Mol Ther 2024; 32:1000-1015. [PMID: 38414243 PMCID: PMC11163220 DOI: 10.1016/j.ymthe.2024.02.026] [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: 09/20/2023] [Revised: 01/19/2024] [Accepted: 02/24/2024] [Indexed: 02/29/2024] Open
Abstract
Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate (NHP) model of HIV infection, we evaluated two CAR-based gene therapy approaches. In the ACT approach, we used cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells, which led to minimal control of the virus. In our stem cell-based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion, which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest that a stem cell-based CAR T cell approach may be superior in generating long-term persistence and functional antiviral responses against HIV infection.
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Affiliation(s)
- Mayra A Carrillo
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Anjie Zhen
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Wenli Mu
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Valerie Rezek
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Heather Martin
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Christopher W Peterson
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | - Hans-Peter Kiem
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | - Scott G Kitchen
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
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7
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Zhang T, Tai Z, Miao F, Zhang X, Li J, Zhu Q, Wei H, Chen Z. Adoptive cell therapy for solid tumors beyond CAR-T: Current challenges and emerging therapeutic advances. J Control Release 2024; 368:372-396. [PMID: 38408567 DOI: 10.1016/j.jconrel.2024.02.033] [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: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/23/2024] [Indexed: 02/28/2024]
Abstract
Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) is a highly specific anti-tumor immunotherapy that has shown promise in the treatment of hematological malignancies. However, there has been a slow progress toward the treatment of solid tumors owing to the complex tumor microenvironment that affects the localization and killing ability of the CAR cells. Solid tumors with a strong immunosuppressive microenvironment and complex vascular system are unaffected by CAR cell infiltration and attack. To improve their efficacy toward solid tumors, CAR cells have been modified and upgraded by "decorating" and "pruning". This review focuses on the structure and function of CARs, the immune cells that can be engineered by CARs and the transformation strategies to overcome solid tumors, with a view to broadening ideas for the better application of CAR cell therapy for the treatment of solid tumors.
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Affiliation(s)
- Tingrui Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; Medical Guarantee Center, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China; Department of Pharmacy, First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Fengze Miao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China
| | - Xinyue Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China
| | - Jiadong Li
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China
| | - Hua Wei
- Medical Guarantee Center, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China.
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China; School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443, China.
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Prasongtanakij S, Preedagasamzin S, Jittorntrum B, Anurathapan U, Puavilai T, Niparuck P, Chantrathammachart P, Piyajaroenkij T, Uaesoontrachoon K, Uchibori R, Ozawa K, Ohmine K, Hongeng S. Cytotoxicity and exhaustion markers of chimeric antigen receptor T cells targeting BCMA in multiple myeloma cell lines between patients and healthy donors. Eur J Haematol 2024; 112:248-256. [PMID: 37222081 DOI: 10.1111/ejh.14007] [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: 04/09/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/25/2023]
Abstract
OBJECTIVES Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. METHODS BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA-ECTM and K562, respectively. RESULTS BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA-ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM-3, LAG-3, and PD1. CONCLUSIONS Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA-expressing cells in vitro and had similar levels of exhaustion markers among different populations.
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Affiliation(s)
- Somsak Prasongtanakij
- Research, Academics and Innovation Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sarinthip Preedagasamzin
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Bunyada Jittorntrum
- Research, Academics and Innovation Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Teeraya Puavilai
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pimjai Niparuck
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Thanakrit Piyajaroenkij
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Ryosuke Uchibori
- Division of Immuno-Gene & Cell Therapy, Jichi Medical University, Tochigi-ken, Japan
| | - Keiya Ozawa
- Division of Immuno-Gene & Cell Therapy, Jichi Medical University, Tochigi-ken, Japan
| | - Ken Ohmine
- Division of Immuno-Gene & Cell Therapy, Jichi Medical University, Tochigi-ken, Japan
- Department of Medicine, School of Medicine, Jichi Medical University, Tochigi-ken, Japan
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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9
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Agrawal V, Murphy L, Pourhassan H, Pullarkat V, Aldoss I. Optimizing CAR-T cell therapy in adults with B-cell acute lymphoblastic leukemia. Eur J Haematol 2024; 112:236-247. [PMID: 37772976 DOI: 10.1111/ejh.14109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/30/2023]
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated unprecedented success in the treatment of various hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Currently, there are two FDA-approved CD19-directed CAR-T cell products for the treatment of adults with R/R B-ALL. Despite high remission rates following CD19 CAR-T cell therapy in R/R B-ALL, remission durability remains limited in most adult patients, with relapse observed frequently in the absence of additional consolidation therapy. Furthermore, the burden of CAR-T cell toxicity remains significant in adults with R/R B-ALL and further limits the wide utilization of this effective therapy. In this review, we discuss patient and disease factors that are linked to CAR-T cell therapy outcomes in R/R B-ALL and strategies to optimize durability of response to reduce relapse and mitigate toxicity in the adult population. We additionally discuss future approaches being explored to maximize the benefit of CAR-T in adults with B-ALL.
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Affiliation(s)
- Vaibhav Agrawal
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California, USA
| | - Lindsey Murphy
- Department of Pediatrics, City of Hope National Medical Center, Duarte, California, USA
| | - Hoda Pourhassan
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California, USA
| | - Vinod Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California, USA
| | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California, USA
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10
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Niederhuber JE. The microbiome and cancer immunotherapy. CLINICAL IMMUNO-ONCOLOGY 2024:223-236.e4. [DOI: 10.1016/b978-0-323-87763-3.00020-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Acharya L, Garg A, Rai M, Kshetri R, Grewal US, Dhakal P. Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19. J Investig Med 2024; 72:32-46. [PMID: 37497999 DOI: 10.1177/10815589231191811] [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] [Indexed: 07/28/2023]
Abstract
Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.
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Affiliation(s)
- Luna Acharya
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Alpana Garg
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Manoj Rai
- Department of Internal Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Rupesh Kshetri
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Udhayvir S Grewal
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Prajwal Dhakal
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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12
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Testa U, Sica S, Pelosi E, Castelli G, Leone G. CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia. Mediterr J Hematol Infect Dis 2024; 16:e2024010. [PMID: 38223477 PMCID: PMC10786140 DOI: 10.4084/mjhid.2024.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 12/14/2023] [Indexed: 01/16/2024] Open
Abstract
Treatment of refractory and relapsed (R/R) B acute lymphoblastic leukemia (B-ALL) is an unmet medical need in both children and adults. Studies carried out in the last two decades have shown that autologous T cells engineered to express a chimeric antigen receptor (CAR-T) represent an effective technique for treating these patients. Antigens expressed on B-cells, such as CD19, CD20, and CD22, represent targets suitable for treating patients with R/R B-ALL. CD19 CAR-T cells induce a high rate (80-90%) of complete remissions in both pediatric and adult R/R B-ALL patients. However, despite this impressive rate of responses, about half of responding patients relapse within 1-2 years after CAR-T cell therapy. Allo-HSCT after CAR-T cell therapy might consolidate the therapeutic efficacy of CAR-T and increase long-term outcomes; however, not all the studies that have adopted allo-HSCT as a consolidative treatment strategy have shown a benefit deriving from transplantation. For B-ALL patients who relapse early after allo-HSCT or those with insufficient T-cell numbers for an autologous approach, using T cells from the original stem cell donor offers the opportunity for the successful generation of CAR-T cells and for an effective therapeutic approach. Finally, recent studies have introduced allogeneic CAR-T cells generated from healthy donors or unmatched, which are opportunely manipulated with gene editing to reduce the risk of immunological incompatibility, with promising therapeutic effects.
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Affiliation(s)
| | - Simona Sica
- Dipartimento Di Diagnostica per Immagini, Radioterapia Oncologica Ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy. Sezione Di Ematologia
- Dipartimento Di Scienze Radiologiche Ed Ematologiche, Università Cattolica Del Sacro Cuore, Roma, Italy
| | | | | | - Giuseppe Leone
- Dipartimento Di Scienze Radiologiche Ed Ematologiche, Università Cattolica Del Sacro Cuore, Roma, Italy
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13
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Locatelli F, Shah B, Thomas T, Velasco K, Adedokun B, Aldoss I, Gore L, Hoelzer D, Bassan R, Park JH, Boissel N, Kantarjian H. Incidence of CD19-negative relapse after CD19-targeted immunotherapy in R/R BCP acute lymphoblastic leukemia: a review. Leuk Lymphoma 2023; 64:1615-1633. [PMID: 37526512 DOI: 10.1080/10428194.2023.2232496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/25/2023] [Indexed: 08/02/2023]
Abstract
There are inconsistencies in the reporting of CD19 antigen status following treatment with CD19-targeted therapies. A majority of evidence comes from studies reporting small sample sizes. In this review, we systematically summarize published studies that have reported rates of CD19-negative relapse after treatment with either blinatumomab or CD19-directed CAR T-cell therapy and report the rates of CD19-negative relapse when evaluated in a standardized way across trials. CD19-negative relapse appears to occur more commonly in relapses following CAR T-cell therapy compared with blinatumomab, whether proportions are calculated among all treated patients (8.7% vs 4.5%) or among patients who relapse (30% vs 22.5%). The median (range) duration of follow-up was 29.3 (17.4-50.8) and 20.4 (6.9-49.0) months for publications on blinatumomab (n = 10) and CAR T-cell therapies (n = 23), respectively. There is a need for standardized reporting of CD19 antigen status in the setting of relapse following novel immunotherapies to inform clinical practice.
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Affiliation(s)
- Franco Locatelli
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Catholic University of the Sacred Heart, Rome, Italy
| | - Bijal Shah
- Moffitt Cancer Center, Tampa, Florida, USA
| | | | | | | | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
| | - Lia Gore
- Children's Hospital Colorado and University of Colorado Cancer Center, Colorado, USA
| | | | - Renato Bassan
- Hematology Unit, Azienda Ulss3 Serenissima, Ospedale dell'Angelo, Venice, Italy
| | - Jae H Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Nicolas Boissel
- Hematology Adolescent and Young Adult Unit, Saint-Louis Hospital, AP-HP; URP-3518, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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14
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Smith R, Shen R. Complexities in comparing the impact of costimulatory domains on approved CD19 CAR functionality. J Transl Med 2023; 21:515. [PMID: 37518011 PMCID: PMC10387212 DOI: 10.1186/s12967-023-04372-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023] Open
Abstract
Chimeric antigen receptors (CARs) are engineered to target T cells specifically to tumor cells, resulting in the engineered T cell killing the tumor cell. This technology has been developed to target a range of cancers, with the most notable successes in the treatment of B-cell malignancies where four approved therapies, all targeting CD19, are on the market. These four products differ in the costimulation domains, with axicabtagene ciloleucel (Yescarta) and brexucabtagene autoleucel (Tecartus) both utilizing the CD28 costimulation domain whilst tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (Breyanzi) both utilizing the 4-1BB costimulation domain. There are clearly defined differences in how the CD28 and 4-1BB domains signal, yet it is difficult to ascertain which domain affords a superior mechanism of action given many other differences between these products, including overall CAR architecture and manufacturing methods. Additionally, while in vitro and preclinical in vivo studies have compared CARs with different costimulation domains, it remains a challenge to extrapolate differences observed in this biology across different experimental systems to the overall product performance. While there has been extensive preclinical and clinical work looking at CARs with a variety of targeting domains and architectures, this review will focus on the differences between the four marketed anti-CD19 CAR-Ts, with an additional focus on the impact of hinge and transmembrane domain on CAR activity and interaction with the target cell as well as other proteins on the surface of the T-cell.
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Affiliation(s)
| | - Rhine Shen
- Kite Pharma Inc, Santa Monica, CA, 90404, USA
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15
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Shiqi L, Jiasi Z, Lvzhe C, Huailong X, Liping H, Lin L, Qianzhen Z, Zhongtao Y, Junjie S, Zucong C, Yingzi Z, Meiling W, Yunyan L, Linling W, Lihua F, Yingnian C, Wei Z, Yu L, Le L, Youcheng W, Dingsong Z, Yancheng D, Ping Y, Lihua Z, Xiaoping L, Xiaozhuang H, Zhongzheng Z, Zhi Y, Cheng Q, Sanbin W. Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T. Mol Ther Oncolytics 2023; 29:107-117. [PMID: 37215385 PMCID: PMC10196916 DOI: 10.1016/j.omto.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
CD19-targeted chimeric antigen receptor T lymphocytes (CAR-T) has demonstrated a high proportion of complete remission in the treatment of relapsed refractory acute B cell lymphoblastic leukemia (r/r B-ALL). It is of great clinical significance to explore which factors will impact long-term disease-free survival of patients with r/r B-ALL after CAR-T therapy without bridging bone marrow transplantation. Our study found that, in patients with r/r B-ALL without bridging transplantation, the patients' age; infusion dosage; whether they had undergone allo-stem cell transplantation before CAR-T therapy, using CD-19-targeted or CD19/CD22-dual-targeted CAR-T; whether there is fusion gene; tumor burden before therapy; and comorbidity had no significant relationship with their long-term disease-free survival. We found only that CAR-T persistence was highly correlated with patients' long-term disease-free survival. So, we further profiled CAR-T cells using single-cell sequencing and found that there is a specific T cell subset that may be associated with the long-term persistence of CAR-T. Finally, according to the single-cell sequencing results, we established cell production process named PrimeCAR, which shared common signaling pathways with the T cell subset identified. In the preliminary clinical study, prime CAR-Ts yield good persistence in peripheral blood of patients with B-ALL and lymphoma, without observing grade 2 or higher cytokine release syndrome.
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Affiliation(s)
- Li Shiqi
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Zhang Jiasi
- Center for Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Chen Lvzhe
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Xu Huailong
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - He Liping
- Department of Epidemiology and Health Statistics, School of Public Health, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Liu Lin
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Zhang Qianzhen
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Yuan Zhongtao
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Shen Junjie
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Chen Zucong
- The People’s Hospital of Dehong Prefecture, Dehong, Yunnan Province 678400, China
| | - Zhang Yingzi
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Wang Meiling
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Li Yunyan
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Wang Linling
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Fang Lihua
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Chen Yingnian
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Zhu Wei
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Li Yu
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Luo Le
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Wang Youcheng
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Zhang Dingsong
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Dong Yancheng
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Yin Ping
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Zhang Lihua
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Li Xiaoping
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
| | - Hu Xiaozhuang
- Shanghai Tissuebank Biotechnology Co., Ltd., Shanghai 201318, China
| | - Zheng Zhongzheng
- Shanghai Tissuebank Biotechnology Co., Ltd., Shanghai 201318, China
| | - Yang Zhi
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Qian Cheng
- Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China
| | - Wang Sanbin
- Department of Hematology, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming, Yunnan Province 650100, China
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16
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Wu L, Chen J, Cai R, Wang X, Liu Y, Zheng Q, Li L. Difference in Efficacy and Safety of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Containing 4-1BB and CD28 Co-Stimulatory Domains for B-Cell Acute Lymphoblastic Leukemia. Cancers (Basel) 2023; 15:2767. [PMID: 37345104 DOI: 10.3390/cancers15102767] [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: 04/06/2023] [Revised: 05/06/2023] [Accepted: 05/13/2023] [Indexed: 06/23/2023] Open
Abstract
This study quantified the differences in the efficacy and safety of different stimulation domains of anti-CD19 chimeric antigen receptor (CAR) T therapy for B-cell acute lymphoblastic leukemia (B-ALL). Clinical trials related to anti-CD19 CAR T-cell therapy for B-ALL were searched in public databases from database inception to 13 November 2021. The differences in overall survival (OS) and progression-free survival (PFS) of B-ALL patients treated with anti-CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains were compared by establishing a parametric survival function. The overall remission rate (ORR), the proportion of people with minimal residual disease (MRD)-negative complete remission (CR), the incidence of cytokine release syndrome (CRS), and the neurotoxicity across different co-stimulatory domains was assessed using a random-effects model. The correlation between the ORR, MRD-negative CR, PFS, and OS was tested. The results showed that the median OS of anti-CAR T-cell treatment containing 4-1BB and CD28 co-stimulatory domains was 15.0 months (95% CI: 11.0-20.0) and 8.5 months (95% CI: 5.0-14.0), and the median PFS was 7.0 months (95% CI: 4.0-11.5) and 3.0 months (95% CI: 1.5-7.0), respectively. Anti-CD19 CAR T-cells in the 4-1BB co-stimulatory domain showed superior benefits in patients who achieved ORR. The incidence of neurotoxicity was significantly higher in the CD28 co-stimulatory domain of anti-CD19 CAR T-cells than in the 4-1BB co-stimulatory domain. In addition, the ORR and MRD-negative CR were strongly correlated with OS and PFS, and PFS and OS were strongly correlated. The 4-1BB co-stimulatory domain suggested a better benefit-risk ratio than the CD28 co-stimulatory domain in B-ALL.
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Affiliation(s)
- Lijuan Wu
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Junchao Chen
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Ruifen Cai
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Xinrui Wang
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Yixiao Liu
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Qingshan Zheng
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
| | - Lujin Li
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China
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17
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Liu L, Ma C, Zhang Z, Witkowski MT, Aifantis I, Ghassemi S, Chen W. Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse. J Immunother Cancer 2022; 10:e005360. [PMID: 36600553 PMCID: PMC9730379 DOI: 10.1136/jitc-2022-005360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited. METHODS We established a computational model of CAR T-cell therapy to recapitulate key cellular mechanisms and dynamics during treatment with responses of continuous remission (CR), non-response (NR), and CD19-positive (CD19+) and CD19-negative (CD19-) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling. RESULTS We revealed critical determinants related to patient responses at remission, resistance, and relapse. For CR, NR, and CD19+ relapse, the overall functionality of CAR T-cell led to various outcomes, whereas loss of the CD19+ antigen and the bystander killing effect of CAR T-cells may partly explain the progression of CD19- relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction. CONCLUSIONS Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.
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Affiliation(s)
- Lunan Liu
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA
| | - Chao Ma
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA
- Department of Biomedical Engineering, New York University, Brooklyn, New York, USA
| | - Zhuoyu Zhang
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA
| | - Matthew T Witkowski
- Perlmutter Cancer Center, NYU Langone Health, New York City, New York, USA
- Department of Pathology, NYU Langone Health, New York City, New York, USA
| | - Iannis Aifantis
- Perlmutter Cancer Center, NYU Langone Health, New York City, New York, USA
- Department of Pathology, NYU Langone Health, New York City, New York, USA
| | - Saba Ghassemi
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Weiqiang Chen
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA
- Department of Biomedical Engineering, New York University, Brooklyn, New York, USA
- Perlmutter Cancer Center, NYU Langone Health, New York City, New York, USA
- Department of Pathology, NYU Langone Health, New York City, New York, USA
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18
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Zhang Z, Liu L, Ma C, Chen W. A Computational Model of Cytokine Release Syndrome during CAR T-cell Therapy. ADVANCED THERAPEUTICS 2022; 5:2200130. [PMID: 36590643 PMCID: PMC9797206 DOI: 10.1002/adtp.202200130] [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: 06/24/2022] [Indexed: 01/05/2023]
Abstract
Cytokine release syndrome (CRS) is a lethal adverse event in chimeric antigen receptor (CAR) T-cell therapy, hindering this promising therapy for cancers, such as B-cell acute lymphoblastic leukemia (B-ALL). Clinical management of CRS requires a better understanding of its underlying mechanisms. In this study, a computational model of CRS during CAR T-cell therapy is built to depict how the cellular interactions among CAR T-cells, B-ALL cells, and bystander monocytes, as well as the accompanying molecular interactions among various inflammatory cytokines, influence the severity of CRS. The model successfully defines the factors related to severe CRS and studied the effects of immunomodulatory therapy on CRS. The use of the model is also demonstrated as a precision medicine tool to optimize the treatment scheme, including personalized choice of CAR T-cell products and control of switchable CAR T-cell activity, for a more efficient and safer immunotherapy. This new computational oncology model can serve as a precision medicine tool to guide the clinical management of CRS during CAR T cell therapy.
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Affiliation(s)
- Zhuoyu Zhang
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA
| | - Lunan Liu
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA
| | - Chao Ma
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA
| | - Weiqiang Chen
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA
- Department of Biomedical Engineering, New York University, Brooklyn, NY 11201, USA
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA
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19
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Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML. Biomedicines 2022; 10:biomedicines10102441. [PMID: 36289703 PMCID: PMC9598885 DOI: 10.3390/biomedicines10102441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/20/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Following the success of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapies against B-cell malignancies, the CAR T-cell approach is being developed towards other malignancies like acute myeloid leukemia (AML). Treatment options for relapsed AML patients are limited, and the upregulation of the FMS-like tyrosine kinase 3 (FLT3) in malignant T-cells is currently not only being investigated as a prognostic factor, but also as a target for new treatment options. In this review, we provide an overview and discuss different approaches of current anti-FLT3 CAR T-cells under development. In general, these therapies are effective both in vitro and in vivo, however the safety profile still needs to be further investigated. The first clinical trials have been initiated, and the community now awaits clinical evaluation of the approach of targeting FLT3 with CAR T-cells.
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20
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Clinical Strategies for Enhancing the Efficacy of CAR T-Cell Therapy for Hematological Malignancies. Cancers (Basel) 2022; 14:cancers14184452. [PMID: 36139611 PMCID: PMC9496667 DOI: 10.3390/cancers14184452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/31/2022] [Accepted: 09/03/2022] [Indexed: 11/16/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cells have been successfully used for hematological malignancies, especially for relapsed/refractory B-cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. Patients who have undergone conventional chemo-immunotherapy and have relapsed can achieve complete remission for several months with the infusion of CAR T-cells. However, side effects and short duration of response are still major barriers to further CAR T-cell therapy. To improve the efficacy, multiple targets, the discovery of new target antigens, and CAR T-cell optimization have been extensively studied. Nevertheless, the fact that the determination of the efficacy of CAR T-cell therapy is inseparable from the discussion of clinical application strategies has rarely been discussed. In this review, we will discuss some clinical application strategies, including lymphodepletion regimens, dosing strategies, combination treatment, and side effect management, which are closely related to augmenting and maximizing the efficacy of CAR T-cell therapy.
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21
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Wei Z, Cheng Q, Xu N, Zhao C, Xu J, Kang L, Lou X, Yu L, Feng W. Investigation of CRS-associated cytokines in CAR-T therapy with meta-GNN and pathway crosstalk. BMC Bioinformatics 2022; 23:373. [PMID: 36100873 PMCID: PMC9469618 DOI: 10.1186/s12859-022-04917-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Background Chimeric antigen receptor T-cell (CAR-T) therapy is a new and efficient cellular immunotherapy. The therapy shows significant efficacy, but also has serious side effects, collectively known as cytokine release syndrome (CRS). At present, some CRS-related cytokines and their roles in CAR-T therapy have been confirmed by experimental studies. However, the mechanism of CRS remains to be fully understood. Methods Based on big data for human protein interactions and meta-learning graph neural network, we employed known CRS-related cytokines to comprehensively investigate the CRS associated cytokines in CAR-T therapy through protein interactions. Subsequently, the clinical data for 119 patients who received CAR-T therapy were examined to validate our prediction results. Finally, we systematically explored the roles of the predicted cytokines in CRS occurrence by protein interaction network analysis, functional enrichment analysis, and pathway crosstalk analysis. Results We identified some novel cytokines that would play important roles in biological process of CRS, and investigated the biological mechanism of CRS from the perspective of functional analysis. Conclusions 128 cytokines and related molecules had been found to be closely related to CRS in CAR-T therapy, where several important ones such as IL6, IFN-γ, TNF-α, ICAM-1, VCAM-1 and VEGFA were highlighted, which can be the key factors to predict CRS. Supplementary Information The online version contains supplementary material available at 10.1186/s12859-022-04917-2.
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Affiliation(s)
- Zhenyu Wei
- College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China
| | - Qi Cheng
- College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China
| | - Nan Xu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, Institute of Biomedical Engineering and Technology, East China Normal University, No. 3663 North Zhongshan Road, Shanghai, 200065, China.,Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, Shanghai, China
| | - Chengkui Zhao
- College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China
| | - Jiayu Xu
- College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China
| | - Liqing Kang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, Institute of Biomedical Engineering and Technology, East China Normal University, No. 3663 North Zhongshan Road, Shanghai, 200065, China.,Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, Shanghai, China
| | - Xiaoyan Lou
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, Institute of Biomedical Engineering and Technology, East China Normal University, No. 3663 North Zhongshan Road, Shanghai, 200065, China.,Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, Shanghai, China
| | - Lei Yu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, Institute of Biomedical Engineering and Technology, East China Normal University, No. 3663 North Zhongshan Road, Shanghai, 200065, China. .,Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, Shanghai, China.
| | - Weixing Feng
- College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China.
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22
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Sun W, Huang X. Role of allogeneic haematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukaemia in the era of immunotherapy. Chin Med J (Engl) 2022; 135:890-900. [PMID: 34890382 PMCID: PMC9276108 DOI: 10.1097/cm9.0000000000001898] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the standard of care for adult acute lymphoblastic leukemia (ALL) patients. In recent years, with the continuous development of immunotherapy, such as chimeric antigen receptor T cells, blinatumomab, and inotuzumab ozogamicin, a series of vital clinical studies have confirmed its high response rate and favorable outcomes for ALL. Although the emergence of immunotherapy has expanded relapsed or refractory (r/r) ALL patients' opportunities to receive allo-HSCT, allo-HSCT is associated with potential challenges. In this review, the role of allo-HSCT in the treatment of adult ALL in the era of immunotherapy will be discussed.
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Affiliation(s)
- Wei Sun
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
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23
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Qian S, Villarejo-Campos P, Guijo I, Hernández-Villafranca S, García-Olmo D, González-Soares S, Guadalajara H, Jiménez-Galanes S, Qian C. Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects. Front Immunol 2022; 13:841425. [PMID: 35401510 PMCID: PMC8990899 DOI: 10.3389/fimmu.2022.841425] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/02/2022] [Indexed: 12/24/2022] Open
Abstract
Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.
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Affiliation(s)
- Siyuan Qian
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Ismael Guijo
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Damián García-Olmo
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sara González-Soares
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | - Héctor Guadalajara
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Cheng Qian
- Chongqing Precision Biotechnology Co. Ltd, Chongqing, China
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24
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Grover P, Veilleux O, Tian L, Sun R, Previtera M, Curran E, Muffly L. Chimeric antigen receptor T-cell therapy in adults with B-cell acute lymphoblastic leukemia. Blood Adv 2022; 6:1608-1618. [PMID: 34610109 PMCID: PMC8905689 DOI: 10.1182/bloodadvances.2020003482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/02/2021] [Indexed: 11/20/2022] Open
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)-negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.
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Affiliation(s)
- Punita Grover
- Division of Hematology and Oncology, University of Cincinnati Medical Center, Cincinnati, OH
| | - Olivier Veilleux
- Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, CA
| | - Lu Tian
- Department of Health Research and Policy, Stanford University, Stanford, CA
| | - Ryan Sun
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; and
| | | | - Emily Curran
- Division of Hematology and Oncology, University of Cincinnati Medical Center, Cincinnati, OH
| | - Lori Muffly
- Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, CA
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25
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Zhang ZZ, Wang T, Wang XF, Zhang YQ, Song SX, Ma CQ. Improving the ability of CAR-T cells to hit solid tumors: Challenges and strategies. Pharmacol Res 2021; 175:106036. [PMID: 34920118 DOI: 10.1016/j.phrs.2021.106036] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/30/2021] [Accepted: 12/12/2021] [Indexed: 12/14/2022]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is a late-model of immune cell therapy that has been shown to be effective in refractory/recurrent B-cell leukemia and lymphoma. Compared with the traditional anti-tumor methods, CAR-T cell therapy has the advantages of higher specificity, stronger lethality and longer-lasting efficacy. Although CAR-T cells have made significant progress in the treatment of hematologic malignancies, diverse difficulties remain in the treatment of solid tumors, including immune escape due to tumor antigen heterogeneity, preventing entry or limiting the persistence of CAR-T cells by physical or cytokine barriers and along with other immunosuppressive molecule and cells in the tumor microenvironment (TME). Otherwise, the intracellular signaling of CAR also impact on CAR-T cells persistence. Appropriate modification of intracellular costimulatory molecular signal in the structure of CAR or coexpression of CAR and cytokines can provide a way to enhance CAR-T cells activity. Additionally, CAR-T cells dysfunction due to T cell exhaustion is associated with multi-factors, especially transcription factors, such as c-Jun, NR4A. Engineering CAR-T cells to coexpress or knockout transcription factors in favor of TCM memory CAR-T cells differentiation was proved to prolonged the survival of CAR-T cells. Finally, combination of CAR-T cells with oncolytic viruses, nanoparticles or immune checkpoint inhibitors provides an effective measure to improve CAR-T cells function. Here, we discuss all of these advances and challenges and review promising strategies for treating solid tumors. In particular, we also highlight that CAR-T cells have enormous potential to be used in combination with other immunotherapies.
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Affiliation(s)
- Zheng-Zheng Zhang
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China
| | - Tian Wang
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China
| | - Xiao-Feng Wang
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China
| | - Yu-Qing Zhang
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China
| | - Shu-Xia Song
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China.
| | - Cui-Qing Ma
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention for Serious Diseases in Hebei Province, Shijiazhuang 050017, Heibei, China.
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26
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Meir J, Abid MA, Abid MB. State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses. Transplant Cell Ther 2021; 27:973-987. [PMID: 34587552 PMCID: PMC8473073 DOI: 10.1016/j.jtct.2021.09.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/06/2021] [Accepted: 09/19/2021] [Indexed: 02/08/2023]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has shown unprecedented response rates in patients with relapsed/refractory (R/R) hematologic malignancies. Although CAR-T therapy gives hope to heavily pretreated patients, the rapid commercialization and cumulative immunosuppression of this therapy predispose patients to infections for a prolonged period. CAR-T therapy poses distinctive short- and long-term toxicities and infection risks among patients who receive CAR T-cells after multiple prior treatments, often including hematopoietic cell transplantation. The acute toxicities include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The long-term B cell depletion, hypogammaglobulinemia, and cytopenia further predispose patients to severe infections and abrogate the remission success achieved by the living drug. These on-target-off-tumor toxicities deplete B-cells across the entire lineage and further diminish immune responses to vaccines. Early observational data suggest that patients with hematologic malignancies may not mount adequate humoral and cellular responses to SARS-CoV-2 vaccines. In this review, we summarize the immune compromising factors indigenous to CAR-T recipients. We discuss the immunogenic potential of different SARS-CoV-2 vaccines for CAR-T recipients based on the differences in vaccine manufacturing platforms. Given the lack of data related to the safety and efficacy of SARS-CoV-2 vaccines in this distinctively immunosuppressed cohort, we summarize the infection risks associated with Food and Drug Administration-approved CAR-T constructs and the potential determinants of vaccine responses. The review further highlights the potential need for booster vaccine dosing and the promise for heterologous prime-boosting and other novel vaccine strategies in CAR-T recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Affiliation(s)
- Juliet Meir
- Department of Medicine, Westchester Medical Center, Valhalla, New York
| | - Muhammad Abbas Abid
- Department of Hematopathology & Microbiology, The Aga Khan University Hospital, Karachi, Pakistan
| | - Muhammad Bilal Abid
- Divisions of Infectious Diseases and Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
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27
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Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol 2021; 18:715-727. [PMID: 34230645 DOI: 10.1038/s41571-021-00530-z] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2021] [Indexed: 02/06/2023]
Abstract
Chimeric antigen receptors (CARs) are engineered proteins designed to target T cells to cancer cells. To effectively activate the T cells in which they are expressed, CARs must contain a costimulatory domain. The CAR T cell products approved for the treatment of B cell lymphomas and/or acute lymphoblastic leukaemia or multiple myeloma incorporate either a CD28-derived or a 4-1BB-derived costimulatory domain. Almost all other clinically tested CARs also use costimulatory domains from CD28 or 4-1BB. In preclinical experiments, cytokine release is usually greater with CARs containing CD28 versus 4-1BB costimulatory domains; however, constructs with either domain confer similar anticancer activity in mouse models. T cell products expressing CARs with either CD28 or 4-1BB costimulatory domains have been highly efficacious in patients with relapsed haematological malignancies, with anti-CD19 products having similar activity regardless of the source of the costimulatory domain. In large-cohort clinical trials, the rates of neurological toxicities have been higher with CD28-costimulated CARs, although this finding is probably the result of a combination of factors rather than due to CD28 signalling alone. Future preclinical and clinical research should aim to compare different costimulatory domains while controlling for confounding variables. Herein, we provide an overview of T cell costimulation by CD28 and 4-1BB and, using the available preclinical and clinical data, compare the efficacy and toxicity profiles associated with CARs containing either costimulatory domain.
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Affiliation(s)
- Kathryn M Cappell
- Hematology Oncology Fellowship Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
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28
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Qin H, Yang L, Chukinas JA, Shah N, Tarun S, Pouzolles M, Chien CD, Niswander LM, Welch AR, Taylor N, Tasian SK, Fry TJ. Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design. J Immunother Cancer 2021; 9:jitc-2021-003149. [PMID: 34531250 PMCID: PMC8449984 DOI: 10.1136/jitc-2021-003149] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 12/02/2022] Open
Abstract
Background Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown. Methods In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML. Results We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A ‘best-in-class’ lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation. Conclusions CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML. Trial registration number clinicaltrials.gov; NCT03971799.
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Affiliation(s)
- Haiying Qin
- National Institutes of Health, Bethesda, Maryland, USA
| | - Lila Yang
- National Institutes of Health, Bethesda, Maryland, USA
| | - John A Chukinas
- Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nirali Shah
- National Institutes of Health, Bethesda, Maryland, USA
| | | | | | | | - Lisa M Niswander
- Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | | | - Naomi Taylor
- National Institutes of Health, Bethesda, Maryland, USA
| | - Sarah K Tasian
- Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA .,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Terry J Fry
- Division of Hematology/Oncology/BMT, Children's Hospital Colorado, Aurora, Colorado, USA
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29
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Wudhikarn K, Flynn JR, Rivière I, Gönen M, Wang X, Senechal B, Curran KJ, Roshal M, Maslak PG, Geyer MB, Halton EF, Diamonte C, Davila ML, Sadelain M, Brentjens RJ, Park JH. Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy. Blood 2021; 138:531-543. [PMID: 33851211 PMCID: PMC8377478 DOI: 10.1182/blood.2020009515] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 04/13/2021] [Accepted: 03/23/2021] [Indexed: 12/23/2022] Open
Abstract
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.
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Affiliation(s)
- Kitsada Wudhikarn
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Research Unit in Translational Hematology, Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | | | - Kevin J Curran
- Bone Marrow Transplant Service, Department of Pediatrics
- Cellular Therapeutics Center
- Department of Pediatrics
| | | | - Peter G Maslak
- Immunology Laboratory Service, Department of Laboratory Medicine, and
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell College of Medicine, New York, NY
| | - Mark B Geyer
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell College of Medicine, New York, NY
| | | | | | - Marco L Davila
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and
| | - Michel Sadelain
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Renier J Brentjens
- Immunology Laboratory Service, Department of Laboratory Medicine, and
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell College of Medicine, New York, NY
| | - Jae H Park
- Cellular Therapeutics Center
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell College of Medicine, New York, NY
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30
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Dholaria B, Savani BN, Huang XJ, Nagler A, Perales MA, Mohty M. The evolving role of allogeneic haematopoietic cell transplantation in the era of chimaeric antigen receptor T-cell therapy. Br J Haematol 2021; 193:1060-1075. [PMID: 33928630 DOI: 10.1111/bjh.17460] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/15/2021] [Indexed: 01/01/2023]
Abstract
Chimaeric antigen receptor T-cell (CAR T) therapy has revolutionized the management of many haematological malignancies. It is associated with impressive disease responses in relapsed or refractory high-grade B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukaemia (B-ALL) with durable remissions in a subset of patients. Historically, haematopoietic cell transplantation (HCT) has been the standard consolidation strategy for many of these patients who are now being treated with CAR T. Relapses are frequent after CD19 CAR T therapy in B-ALL and consolidation with allogeneic HCT (allo-HCT) may improve survival of patients with high-risk disease. There appears to be a clear difference in B-ALL outcomes between paediatric and adult patients, with the latter having a much higher risk of relapse after CAR T therapy. Late relapses are infrequent in patients with B-NHL and consolidation with allo-HCT may not be needed in patients who achieve a complete remission after CAR T therapy. Future registry-based and prospective studies will hopefully provide the needed data in the future to risk-stratify the recipients of CAR T therapy. Meanwhile, we provide guidance on patient selection and practical issues with performing allo-HCT after CAR T therapy.
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Affiliation(s)
| | - Bipin N Savani
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xiao-Jun Huang
- Peking University Institute of Hematology, Beijing, China
| | - Arnon Nagler
- Chaim Sheba Medical Center, Tel Hashomer, Israel, ALWP Office Hôpital Saint-Antoine, Paris, France.,EBMT ALWP Office Hôpital Saint-Antoine, Paris, France
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mohamad Mohty
- EBMT ALWP Office Hôpital Saint-Antoine, Paris, France.,Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne University, INSERM, UMRs 938, Paris, France
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31
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CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success. BioDrugs 2021; 35:281-302. [PMID: 33826079 DOI: 10.1007/s40259-021-00477-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2021] [Indexed: 12/13/2022]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.
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32
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Wei J, Guo Y, Wang Y, Wu Z, Bo J, Zhang B, Zhu J, Han W. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol 2021; 18:792-804. [PMID: 32999455 PMCID: PMC8115146 DOI: 10.1038/s41423-020-00555-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in the treatment of hematological malignancies. In recent years, fast-growing CAR T clinical trials have actively explored their potential application scenarios. According to the data from the clinicaltrials.gov website, China became the country with the most registered CAR T trials in September 2017. As of June 30, 2020, the number of registered CAR T trials in China has reached 357. In addition, as many as 150 other CAR T trials have been registered on ChiCTR. Although CAR T therapy is flourishing in China, there are still some problems that cannot be ignored. In this review, we aim to systematically summarize the clinical practice of CAR T-cell therapy in China. This review will provide an informative reference for colleagues in the field, and a better understanding of the history and current situation will help us more reasonably conduct research and promote cooperation.
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Affiliation(s)
- Jianshu Wei
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yelei Guo
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yao Wang
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhiqiang Wu
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jian Bo
- Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Bin Zhang
- Department of Hematopoietic Stem Cell Transplantation, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
| | - Jun Zhu
- Key Laboratory of Carcinogenesis and Translational Research, Departments of Lymphoma, Radiology and Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, 100036, China.
| | - Weidong Han
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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33
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Hamilton JAG, Lee MY, Hunter R, Ank RS, Story JY, Talekar G, Sisroe T, Ballak DB, Fedanov A, Porter CC, Eisenmesser EZ, Dinarello CA, Raikar SS, DeGregori J, Henry CJ. Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds. Aging Cell 2021; 20:e13309. [PMID: 33480151 PMCID: PMC7884049 DOI: 10.1111/acel.13309] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 10/17/2020] [Accepted: 12/31/2020] [Indexed: 12/20/2022] Open
Abstract
Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T‐cells and Lat in CD8+ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence.
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Affiliation(s)
- Jamie A. G. Hamilton
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Miyoung Y. Lee
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Rae Hunter
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Raira S. Ank
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Jamie Y. Story
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
- Molecular and Systems Pharmacology Graduate Program Graduate Division of Biological and Biomedical Sciences Laney Graduate School Emory University School of Medicine Atlanta GA USA
| | - Ganesh Talekar
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | | | - Dov B. Ballak
- Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Medicine Radboud University Medical Center Nijmegen The Netherlands
| | - Andrew Fedanov
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Christopher C. Porter
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - Elan Z. Eisenmesser
- Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA
| | - Charles A. Dinarello
- Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Medicine Radboud University Medical Center Nijmegen The Netherlands
| | - Sunil S. Raikar
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Medicine University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Immunology and Microbiology University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Pediatrics University of Colorado Anschutz Medical Campus Aurora CO USA
| | - Curtis J. Henry
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta Atlanta GA USA
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Li H, Yang C, Cheng H, Huang S, Zheng Y. CAR-T cells for Colorectal Cancer: Target-selection and strategies for improved activity and safety. J Cancer 2021; 12:1804-1814. [PMID: 33613769 PMCID: PMC7890323 DOI: 10.7150/jca.50509] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/29/2020] [Indexed: 12/30/2022] Open
Abstract
Chimeric antigen receptor-T (CAR-T) cell immunotherapy is a novel method that is genetically engineered to recruit T cells against malignant disease. Administration of CAR-T cells has led to progress in hematological malignancies, and it has been proposed for solid tumors like colorectal cancer (CRC) for years. However, this method was not living up to expectations for the intrinsic challenges posed to CAR-T cells by solid tumors, which mainly due to the lacking of tumor-restricted antigens and adverse effects following treatment. New approaches are proposed to overcome the multiple challenges to alleviate the difficult situation of CAR-T cells in CRC, including engineering T cells with immune-activating molecules, regional administration of T cell, bispecific T cell engager, and combinatorial target-antigen recognition. In this review, we sum up the current stage of knowledge about target-selection, adverse events like on/off-tumor toxicity, the preclinical and clinical studies of CAR-T therapy, and the characteristics of strategies applied in CRC.
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Affiliation(s)
- Huali Li
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Chao Yang
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Huangrong Cheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shuoyang Huang
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yongbin Zheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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35
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Yang C, Lei W, Xie H, Wu G, Wei J, Liang A, Qian W. Sustained Remission of Relapsed or Refractory Mantle Cell Lymphoma After 4-1BB-Based CD19-Directed CAR-T Therapy. Onco Targets Ther 2020; 13:12163-12168. [PMID: 33268994 PMCID: PMC7701665 DOI: 10.2147/ott.s280535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/06/2020] [Indexed: 12/01/2022] Open
Abstract
Relapsed and refractory (R/R) mantle cell lymphoma (MCL) remains an incurable lymphoma with a poor prognosis. Recently, there are a few studies demonstrating the efficacy of anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy in MCL, including ZUMA-2 study in which CD28-based CAR-T cells were used. However, long-term efficacy and safety associated with 4-1BB-based CAR-T therapy in MCL are not defined well. Here, we report three male patients with R/R classical MCL, who received CD19-directed 4-1BB CAR-T therapy and achieved complete remission, showed mild symptoms of cytokine-release syndrome (CRS) and had no neurological toxicity. During a follow-up of 24–35 months, all three patients remained in complete remission. Persistent B-cell depletion was observed in two patients. Recovery of CD19+ polyclonal B cells was detected in one patient at 6 months after CAR-T cell infusion. Recovery of serum immunoglobulin, including IgG, IgA and IgM, was not observed in two patients at the last follow-up. Only one patient developed herpes zoster, and the other two patients had no serious infection. This is the first report about the efficacy, long-term remission and safety of CD19-directed 4-1BB CAR-T therapy in R/R MCL.
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Affiliation(s)
- Chunmei Yang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, People's Republic of China
| | - Wen Lei
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, People's Republic of China.,Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, People's Republic of China
| | - Hongqiong Xie
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, People's Republic of China
| | - Gongqiang Wu
- Department of Hematology, Dongyang Hospital Affiliated to Wenzhou Medical University, Dongyang 322100, Zhejiang, People's Republic of China
| | - Juying Wei
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, People's Republic of China
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai 200065, People's Republic of China
| | - Wenbin Qian
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, People's Republic of China.,Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, People's Republic of China
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36
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Guo C, Dong E, Lai Q, Zhou S, Zhang G, Wu M, Yue X, Tao Y, Peng Y, Ali J, Lu Y, Fu Y, Lai W, Zhang Z, Ma F, Yao Y, Gou L, Yang H, Yang J. Effective antitumor activity of 5T4-specific CAR-T cells against ovarian cancer cells in vitro and xenotransplanted tumors in vivo. MedComm (Beijing) 2020; 1:338-350. [PMID: 34766126 PMCID: PMC8491242 DOI: 10.1002/mco2.34] [Citation(s) in RCA: 10] [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: 05/20/2020] [Revised: 08/26/2020] [Accepted: 08/28/2020] [Indexed: 02/05/2023] Open
Abstract
Ovarian cancer is considered to be the most lethal gynecologic malignancy, and despite the development of conventional therapies and new therapeutic approaches, the patient's survival time remains short because of tumor recurrence and metastasis. Therefore, effective methods to control tumor progression are urgently needed. The oncofetal tumor-associated antigen 5T4 (trophoblast glycoprotein, TPBG) represents an appealing target for adoptive T-cell immunotherapy as it is highly expressed on the surface of various tumor cells, has very limited expression in normal tissues, and spreads widely in malignant tumors throughout their development. In this study, we generated second-generation human chimeric antigen receptor (CAR) T cells with redirected specificity to 5T4 (5T4 CAR-T) and demonstrated that these CAR-T cells can elicit lytic cytotoxicity in targeted tumor cells, in addition to the secretion of cytotoxic cytokines, including IFN-γ, IL-2, and GM-CSF. Furthermore, adoptive transfer of 5T4 CAR-T cells significantly delayed tumor formation in xenografts of peritoneal and subcutaneous animal models. These results demonstrate the potential efficacy and feasibility of 5T4 CAR-T cell immunotherapy and provide a theoretical basis for the clinical study of future immunotherapies targeting 5T4 for ovarian cancer.
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Affiliation(s)
- Cuiyu Guo
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - E Dong
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Qinhuai Lai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Shijie Zhou
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Guangbing Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Mengdan Wu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Xiaozhu Yue
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Yiran Tao
- West China‐California Research Center for Predictive Intervention MedicineWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Yujia Peng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Jamel Ali
- Department of Chemical and Biomedical EngineeringFAMU‐FSU College of EngineeringTallahasseeFlorida
| | - Ying Lu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Yuyin Fu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Weirong Lai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Zhixiong Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Fanxin Ma
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Yuqin Yao
- Healthy Food Evaluation Research Center/Sichuan UniversityWest China School of Public Health and West China Fourth HospitalChengduPeople's Republic of China
| | - Lantu Gou
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Hanshuo Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
| | - Jinliang Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengduSichuanPeople's Republic of China
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Sadeqi Nezhad M, Seifalian A, Bagheri N, Yaghoubi S, Karimi MH, Adbollahpour-Alitappeh M. Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment? Front Immunol 2020; 11:603237. [PMID: 33324420 PMCID: PMC7727445 DOI: 10.3389/fimmu.2020.603237] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission. Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases. Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells. CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions. The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events. Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell. This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them. Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases. However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells. CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use. The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.
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Affiliation(s)
- Muhammad Sadeqi Nezhad
- Department of Clinical Laboratory Science, Young Researchers and Elites Club, Gorgan Branch, Islamic Azad University, Gorgan, Iran.,Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Gorgan, Iran
| | - Alexander Seifalian
- Nanotechnology & Regenerative Medicine Commercialization Centre (Ltd), The London BioScience Innovation Centre, London, United Kingdom
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sajad Yaghoubi
- Department of Clinical Microbiology, Iranshahr University of Medical Sciences, Iranshahr, Iran
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38
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Anagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. LANCET HAEMATOLOGY 2020; 7:e816-e826. [PMID: 33091355 DOI: 10.1016/s2352-3026(20)30277-5] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. METHODS We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. FINDINGS From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I2=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I2=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I2=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I2=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I2=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. INTERPRETATION The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. FUNDING National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.
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Affiliation(s)
- Theodora Anagnostou
- Department of Medicine, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Irbaz B Riaz
- Division of Haematology, Mayo Clinic, Rochester, MN, USA
| | - Shahrukh K Hashmi
- Division of Haematology, Mayo Clinic, Rochester, MN, USA; Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | | | - Saad S Kenderian
- Division of Haematology, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA; T-Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
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39
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The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma. Cytotherapy 2020; 22:214-226. [PMID: 32305113 DOI: 10.1016/j.jcyt.2020.01.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 12/24/2022]
Abstract
Our objective was to summarize the side effect of chimeric antigen receptor (CAR)-T cell therapy in patients with acute lymphocytic leukemia (ALL) and lymphoma. Two independent reviewers extracted relevant data. A total of 35 hematologic malignancy studies with CD19 CAR-T cell were included (1412 participants). Severe cytokine release syndrome (sCRS) proportion was experienced by 18.5% (95% confidence interval [CI], 0.128-0.259; P = 0.000) of 982 patients with the National Cancer Institute/Lee/common terminology criteria for adverse events grading system. The pooled neurotoxicity proportion was 21.7% (95% CI, 0.167-0.287; P = 0.000) of 747 patients with the same grading system. For all of the 25 clinical trials with the same grading system, subgroup analysis was performed. Based on the different disease type, a pooled prevalence of 35.7% was observed with event rate (ER) of 0.358 (95% CI, 0.289-0.434; P = 0.000) for ALL in 12 clinical trials. For lymphoma, a pooled prevalence of 13% was observed with ER of 0.073 (95% CI, 0.028-0.179; P = 0.000) in eight clinical trials. It was demonstrated that the patients who were older than 18 years of age have the lower sCRS incidence of 16.1% (95% CI, 0.110-0.250; P = 0.000) compared with 28.6% of the remaining population who were younger than 18 years of age (95% CI, 0.117-0.462: P = 0.023) in our analysis. Based on the different co-stimulatory domain, the sCRS of 16.5% was observed with ER of 0.175 (95% CI, 0.090-0.312; P = 0.000) for 4-1BB. The sCRS of 22.2% was observed with ER of 0.193 (95% CI, 0.107-0.322; P = 0.000) for CD28. For both the CD28 and 4-1BB, the sCRS of 17.3% was observed with ER of 0.170 (95% CI, 0.067-0.369; P = 0.003). Sub-analysis sCRS of the impact with cell dose and specific disease indication were also demonstrated. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. These results are helpful for physicians, patients and the other stakeholders to understand the adverse events and to further promote the improvement of CAR-T cell therapy in the future.
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40
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Russo E, Nannini G, Dinu M, Pagliai G, Sofi F, Amedei A. Exploring the food-gut axis in immunotherapy response of cancer patients. World J Gastroenterol 2020; 26:4919-4932. [PMID: 32952339 PMCID: PMC7476177 DOI: 10.3748/wjg.v26.i33.4919] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/16/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
Nowadays, immunotherapy is widely used to treat different cancer types as it boosts the body's natural defenses against the malignancy, with lower risk of adverse events compared to the traditional treatments. The immune system is able to control cancer growth but, unfortunately, many cancers take advantage of immune checkpoints pathways for the immune evasion. An intricate network of factors including tumor, host and environmental variables influence the individual response to immune checkpoints’ inhibitors. Between them, the gut microbiota (GM) has recently gained increasing attention because of its emerging role as a modulator of the immune response. Several studies analyzed the diversities between immunotherapy-sensitive and immunotherapy-resistant cohorts, evidencing that particular GM profiles were closely associated to treatment effect. In addition, other data documented that interventional GM modulation could effectively enhance efficacy and relieve resistance during immunotherapy treatment. Diet represents one of the major GM determinants, and ongoing studies are examining the role of the food-gut axis in immunotherapy treatment. Here, we review recent studies that described how variations of the GM affects patient’s responsivity to anti-cancer immunotherapy and how diet-related factors impact on the GM modulation in cancer, outlining potential future clinical directions of these recent findings.
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Affiliation(s)
- Edda Russo
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
| | - Giulia Nannini
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
| | - Monica Dinu
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
| | - Giuditta Pagliai
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
| | - Francesco Sofi
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50139, Italy
| | - Amedeo Amedei
- Department of Clinical and Experimental Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
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41
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Fu Z, Zhou J, Chen R, Jin Y, Ni T, Qian L, Xiao C. Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. Oncol Lett 2020; 20:36. [PMID: 32802160 PMCID: PMC7412636 DOI: 10.3892/ol.2020.11897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/19/2020] [Indexed: 12/24/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cells have an unprecedented positive curative effect for hematological malignances. Most notably, cluster of differentiation 19 (CD19) CAR T-cell therapy for pediatric acute lymphoblastic leukemia is associated with a high complete remission rate and has aroused considerable attention in the medical field. However, it also causes a series of adverse reactions and increases the risk of recurrence. The present review examines the results of CD19 CAR T-cell therapy and lists its adverse effects. In addition, some of the mechanisms of recurrence are characterized and applicable strategies to address this challenging problem are proposed.
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Affiliation(s)
- Zexin Fu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China.,Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Jinlei Zhou
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China.,Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Rui Chen
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China.,Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Yihua Jin
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China.,Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Ting Ni
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China.,Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Lingbo Qian
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
| | - Chi Xiao
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
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Rubinstein JD, Krupski C, Nelson AS, O'Brien MM, Davies SM, Phillips CL. Chimeric Antigen Receptor T Cell Therapy in Patients with Multiply Relapsed or Refractory Extramedullary Leukemia. Biol Blood Marrow Transplant 2020; 26:e280-e285. [PMID: 32755637 DOI: 10.1016/j.bbmt.2020.07.036] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 12/29/2022]
Abstract
Autologous CD19-directed chimeric antigen receptor T lymphocyte (CAR-T) therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B cell precursor acute lymphoblastic leukemia (B-ALL). Experience using this therapy in pediatric patients with extramedullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). We infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel. Six patients had isolated central nervous system (CNS) leukemia, and 1 patient had an isolated testicular relapse. An initial complete response was seen in all patients, with 5 patients remaining in CAR-T-induced remission at a median of 18 months from first infusion. Reversible ICANS was seen in 1 patient with CNS leukemia. Durable B cell aplasia occurred in 3 patients, with a median time to B cell recovery of 6.5 months in the other patients. These data suggest that CAR-T therapy has promising safety and efficacy in treating EM leukemia, although definitive conclusions are limited by the small size of the cohort and limited follow-up period.
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Affiliation(s)
- Jeremy D Rubinstein
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
| | - Christa Krupski
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Adam S Nelson
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Maureen M O'Brien
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Stella M Davies
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Christine L Phillips
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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43
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Yang S, Cao B, Zhou G, Zhu L, Wang L, Zhang L, Kwok HF, Zhang Z, Zhao Q. Targeting B7-H3 Immune Checkpoint With Chimeric Antigen Receptor-Engineered Natural Killer Cells Exhibits Potent Cytotoxicity Against Non-Small Cell Lung Cancer. Front Pharmacol 2020; 11:1089. [PMID: 32848731 PMCID: PMC7406658 DOI: 10.3389/fphar.2020.01089] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/03/2020] [Indexed: 01/27/2023] Open
Abstract
Chimeric antigen receptor (CAR)-modified natural killer (NK) cell therapy represents a kind of promising anti-cancer treatment because CAR renders NK cells activation and recognition specificity toward tumor cells. An immune checkpoint molecule, B7-H3, plays an inhibitory role in modulation of NK cells. To enhance NK cell functions, we generated NK-92MI cells carrying anti-B7-H3 CAR by lentiviral transduction. The expression of anti-B7-H3 CAR significantly enhanced the cytotoxicity of NK-92MI cells against B7-H3-positive tumor cells. In accordance with enhanced cytotoxicity, the secretions of perforin/granzyme B and expression of CD107a were highly elevated in anti-B7-H3 CAR-NK-92MI cells. Moreover, compared to unmodified NK-92MI cells, anti-B7-H3 CAR-NK-92MI cells effectively limited tumor growth in mouse xenografts of non-small cell lung cancer and significantly prolonged the survival days of mice. This study provides the rationale and feasibility of B7-H3-specific CAR-NK cells for application in adoptive cancer immunotherapy.
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Affiliation(s)
- Shuo Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Bihui Cao
- Department of Radiology, Translational Medicine Center and Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenviroment, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guangyu Zhou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Lipeng Zhu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Lu Wang
- Department of Radiology, Translational Medicine Center and Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenviroment, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li Zhang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Zhenfeng Zhang
- Department of Radiology, Translational Medicine Center and Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenviroment, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qi Zhao
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
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44
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Wang L, Tan Su Yin E, Zhao H, Ni F, Hu Y, Huang H. CAR-T cells: the Chinese experience. Expert Opin Biol Ther 2020; 20:1293-1308. [PMID: 32605454 DOI: 10.1080/14712598.2020.1790521] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Chimeric antigen receptor T (CAR-T) cells are harnessed to identify and lyse malignant cells specifically, efficiently, and independently of the major histocompatibility complex (MHC). As a result, prognoses of relapsed or refractory (R/R) B cell hematological malignancies as well as limited types of solid tumors, have been ameliorated to a great extent. In China, a rising number of clinical trials that contribute to the development of novel CAR-T therapeutic strategies have been conducted on an extensive scale. AREAS COVERED We summarize registered clinical trials related to CAR-T therapy conducted in China by evaluating various parameters such as distribution, study phase, CAR structure, target antigen, and disease. The efficacy, toxicity, and, more importantly, the new strategies for optimization of CAR-T therapy of Chinese studies and clinical trials are elaborated in detail. EXPERT OPINION In terms of the number of CAR-T clinical trials, China is second to the USA, registering approximately 33% of trials worldwide. China's extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy.
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Affiliation(s)
- Linqin Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Elaine Tan Su Yin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Houli Zhao
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Fang Ni
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Yongxian Hu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
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45
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Alizadeh M, Safarzadeh A, Hoseini SA, Piryaei R, Mansoori B, Hajiasgharzadeh K, Baghbanzadeh A, Baradaran B. The potentials of immune checkpoints for the treatment of blood malignancies. Crit Rev Oncol Hematol 2020; 153:103031. [PMID: 32622320 DOI: 10.1016/j.critrevonc.2020.103031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/11/2020] [Accepted: 06/11/2020] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoints are the regulators of the immune system, which include stimulatory and inhibitory receptors. They play substantial roles in the maintenance of immune system homeostasis and the prevention of autoimmunity and cancer. In the current review, immune checkpoints roles are surveyed in the initiation, progression, and treatment of blood malignancies. The significant roles of immune checkpoints are discussed as clinical markers in the diagnosis and prognosis of a plethora of blood malignancies and also as potential targets for the treatment of these malignancies. It could be concluded that the regulation of immune checkpoints in various blood cancers can be employed as a novel strategy to obtain effective results in leukemia treatment and introduce immune checkpoint inhibitors as sufficient weapons against blood cancers in the future.
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Affiliation(s)
- Mohsen Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Safarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Seyed Ali Hoseini
- Department of Genetic, Faculty of Basic Sciences, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Reza Piryaei
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Behzad Mansoori
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | | | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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46
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Zhao X, Yang J, Zhang X, Lu XA, Xiong M, Zhang J, Zhou X, Qi F, He T, Ding Y, Hu X, De Smet F, Lu P, Huang X. Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia. MOLECULAR THERAPY-ONCOLYTICS 2020; 18:272-281. [PMID: 32728615 PMCID: PMC7378699 DOI: 10.1016/j.omto.2020.06.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/19/2020] [Indexed: 12/31/2022]
Abstract
CD19-directed chimeric antigen receptor-T (CAR-T) cells with a 4-1BB or CD28 co-stimulatory domain have shown impressive antitumor activity against relapsed or refractory B cell acute lymphoblastic leukemia (r/r B-ALL). However, a parallel comparison of their performances in r/r B-ALL therapy has not been sufficiently reported. Here, we manufactured 4-1BB- and CD28-based CD19 CAR-T cells using the same process technology and evaluated their efficacy and safety in r/r B-ALL therapy based on pre-clinical and exploratory clinical investigations. In B-ALL-bearing mice, a similar antitumor effect and CAR-T kinetics in peripheral blood were observed at the CAR-T dose of 1 × 107/mouse. However, when the dose was decreased to 1 × 106/mouse, 4-1BB CAR-T cells were more potent in eradicating tumor cells and showed longer persistence than CD28 CAR-T cells. Retrospective analysis of an exploratory clinical study that used 4-1BB- or CD28-based CAR-T cells to treat r/r B-ALL was performed. Compared with CD28 CAR-T cells, 4-1BB CAR-T cells resulted in higher antitumor efficacy and less severe adverse events. This study demonstrated that the performance of 4-1BB CAR-T cells was superior to that of CD28 CAR-T cells in suppressing CD19+ B-ALL, at least under our manufacturing process.
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Affiliation(s)
- Xiangyu Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China
| | - Junfang Yang
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Xian Zhang
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Xin-An Lu
- Immunochina Pharmaceuticals Co., Ltd., Beijing 100089, China
| | - Min Xiong
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Jianping Zhang
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Xiaosu Zhou
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Feifei Qi
- Immunochina Pharmaceuticals Co., Ltd., Beijing 100089, China
| | - Ting He
- Immunochina Pharmaceuticals Co., Ltd., Beijing 100089, China
| | - Yanping Ding
- Immunochina Pharmaceuticals Co., Ltd., Beijing 100089, China
| | - Xuelian Hu
- Immunochina Pharmaceuticals Co., Ltd., Beijing 100089, China
| | - Floris De Smet
- Sartorius Stedim North America, Inc., 565 Johnson Avenue Bohemia, New York, NY 11716, USA
| | - Peihua Lu
- Lu Daopei Hospital, Langfang, Hebei 065201, China.,Lu Daopei Institute of Hematology, Beijing 100176, China
| | - Xiaojun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, No. 11 South Street of Xizhimen, Xicheng District, Beijing 100044, China.,Peking-Tsinghua Center for Life Sciences, Beijing 100871, China
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47
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Nie Y, Lu W, Chen D, Tu H, Guo Z, Zhou X, Li M, Tu S, Li Y. Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies. Biomark Res 2020; 8:18. [PMID: 32514351 PMCID: PMC7254656 DOI: 10.1186/s40364-020-00197-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy, especially anti-CD19 CAR T cell therapy, has shown remarkable anticancer activity in patients with relapsed/refractory acute lymphoblastic leukemia, demonstrating an inspiring complete remission rate. However, with extension of the follow-up period, the limitations of this therapy have gradually emerged. Patients are at a high risk of early relapse after achieving complete remission. Although there are many studies with a primary focus on the mechanisms underlying CD19- relapse related to immune escape, early CD19+ relapse owing to poor in vivo persistence and impaired efficacy accounts for a larger proportion of the high relapse rate. However, the mechanisms underlying CD19+ relapse are still poorly understood. Herein, we discuss factors that could become obstacles to improved persistence and efficacy of CAR T cells during production, preinfusion processing, and in vivo interactions in detail. Furthermore, we propose potential strategies to overcome these barriers to achieve a reduced CD19+ relapse rate and produce prolonged survival in patients after CAR T cell therapy.
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Affiliation(s)
- Yuru Nie
- Second Clinical Medical College, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Weiqing Lu
- Second Clinical Medical College, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Daiyu Chen
- Second Clinical Medical College, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Huilin Tu
- Second Clinical Medical College, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Zhenling Guo
- Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Xuan Zhou
- Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Meifang Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Sanfang Tu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong Province China
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48
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Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model. MOLECULAR THERAPY-ONCOLYTICS 2020; 18:37-46. [PMID: 32637579 PMCID: PMC7321814 DOI: 10.1016/j.omto.2020.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/22/2020] [Indexed: 12/29/2022]
Abstract
The anti-CD19 chimeric antigen receptor (CAR) T cells showed excellent effect against acute lymphoblastic leukemia (ALL) in bone marrow (BM) in clinical trials. However, it remains to be elucidated whether the CD19 CAR T cell therapy is effective for ALL cells in central nervous system (CNS) because the patients with isolated or advanced CNS disease were excluded from clinical trials of systemic intravenous (i.v.) delivery of CAR T cells. Therefore, the preclinical evaluation for the efficacy of CAR T cell therapy against ALL cells in CNS is essential for clinical application. We evaluated the effect and adverse reaction of CD19 CAR T cells against ALL in CNS using a xenograft mouse model by i.v. or intra-cerebroventricular (i.c.v.) delivery of CAR T cells. Injection of piggyBac CD19 CAR T cells by i.v. had partial effects, whereas all CAR T i.c.v.-delivered mice had eliminated ALL in CNS. Although some CAR T i.c.v.-delivered mice showed transient changes of clinical symptoms during the first few days after treatment, none of CAR T i.c.v.-delivered mice displayed fatal adverse events. In this study, we demonstrated that direct delivery into CNS of CAR T cells is a possible therapeutic approach with the xenograft mouse model.
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49
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Fulcher J, Leung E, Christou G, Bredeson C, Sabloff M. Selecting the optimal targeted therapy for relapsed B-acute lymphoblastic leukemia. Leuk Lymphoma 2020; 61:2271-2273. [PMID: 32427017 DOI: 10.1080/10428194.2020.1761965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Jill Fulcher
- Division of Hematology, Department of Medicine, University of Ottawa and Ottawa Health Research Institute, Ottawa, Canada
| | - Eugene Leung
- Division of Nuclear Medicine, Department of Medicine, University of Ottawa and Ottawa Health Research Institute, Ottawa, Canada
| | - Grace Christou
- Division of Hematology, Department of Medicine, University of Ottawa and Ottawa Health Research Institute, Ottawa, Canada
| | - Christopher Bredeson
- Division of Hematology, Department of Medicine, University of Ottawa and Ottawa Health Research Institute, Ottawa, Canada
| | - Mitchell Sabloff
- Division of Hematology, Department of Medicine, University of Ottawa and Ottawa Health Research Institute, Ottawa, Canada
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50
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Danylesko I, Chowers G, Shouval R, Besser MJ, Jacoby E, Shimoni A, Nagler A, Avigdor A. Treatment with anti CD19 chimeric antigen receptor T cells after antibody-based immunotherapy in adults with acute lymphoblastic leukemia. Curr Res Transl Med 2019; 68:17-22. [PMID: 31882377 DOI: 10.1016/j.retram.2019.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 12/10/2019] [Indexed: 01/24/2023]
Abstract
PURPOSE OF THE STUDY The prognosis of patients with relapsed/refractory precursor B-acute lymphoblastic leukemia (ALL) is dismal. Antibody-based therapies, such as blinatumomab or inotuzumab ozogamycin (IO) have led to improved outcomes. The impact of prior immunotherapy on chimeric antigen receptor (CAR) T-Cell therapeutic efficacy and toxicity is unknown. METHODS We describe a case series of ALL patients with prior exposure to blinatumomab or IO, who were treated with anti-CD19 CAR T cells with CD28 co-stimulatory domain (NCT02772198). We then review the literature on CAR-T post antibody-based therapy with either antibodies. RESULTS Five adult patients with B-ALL were included. Three had active disease, and two were in morphological complete remission (CR) with minimal residual disease (MRD+). Therapy before CAR-T included blinatumomab (3/5 [60 %]) and IO (3/5 [60 %]), with one patient receiving both. One patient experienced severe cytokine release syndrome and central nervous system toxicity and subsequently died. At 28 days following treatment, two patients achieved CR with MRD negativity, and two had an MRD + CR. Two patients received allogeneic hematopoietic stem cell transplantation. At a median of 10 months (range, 5-26, three out of the four patients are still in CR, and one relapsed. The literature review identified a deficiency on data on the influence of blinatumumab and IO on outcomes post CAR-T therapy. CONCLUSIONS CD19 CAR T-cell therapy after treatment with blinatumomab and/or IO in patients with relapsed/refractory B-ALL is feasible and results in promising response rates in this case series. Future trails should specifically address outcomes in this population.
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Affiliation(s)
- Ivetta Danylesko
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Guy Chowers
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Roni Shouval
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal J Besser
- Ella Lemelbaum Institute for Immuno Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Elad Jacoby
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Avichai Shimoni
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Arnon Nagler
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Abraham Avigdor
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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