دورية أكاديمية
Stealth transgenes enable CAR-T cells to evade host immune responses.
| العنوان: | Stealth transgenes enable CAR-T cells to evade host immune responses. |
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| المؤلفون: | Grauwet K; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Berger T; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA., Kann MC; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA., Silva H; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA., Larson R; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Leick MB; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Bailey SR; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Bouffard AA; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA., Millar D; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA., Gallagher K; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA., Turtle CJ; Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA., Frigault MJ; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Maus MV; Cellular Immunotherapy Program, Krantz Family Center for Cancer Research, Massachusetts General Hosptial, Charlestown, Massachusetts, USA mvmaus@mgh.harvard.edu.; Harvard Medical School, Boston, Massachusetts, USA.; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. |
| المصدر: | Journal for immunotherapy of cancer [J Immunother Cancer] 2024 May 09; Vol. 12 (5). Date of Electronic Publication: 2024 May 09. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd. Original Publication: London : BioMed Central, 2013- |
| مواضيع طبية MeSH: | Receptors, Chimeric Antigen*/immunology , Receptors, Chimeric Antigen*/genetics , Immunotherapy, Adoptive*/methods, Animals ; Humans ; Mice ; Transgenes ; T-Lymphocytes/immunology |
| مستخلص: | Background: Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing. Methods: In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model. Results: The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 'stealth' CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes. Conclusions: Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients. Competing Interests: Competing interests: KG, MJF, and MVM are inventors of patents related to the stealth technologies described here. CJT has received research funding from Juno Therapeutics, BMS, and Nektar Therapeutics and has the right to receive royalties from Fred Hutch as an inventor on patents related to CAR-T cell therapy that are licensed to Juno Therapeutics/BMS. CJT holds equity in Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, and ArsenalBio, serves on Scientific Advisory Boards of Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio and Century Therapeutics, and serves on ad hoc advisory boards (last 12 months) of Genentech, GlaxoSmithKline and Decheng Capital. MVM is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital and the University of Pennsylvania (some licensed to Novartis). MVM holds equity in TCR2, Century Therapeutics, Genocea, Oncternal, and Neximmune, serves on the Board of Directors of 2Seventy Bio, and has served as a consultant for multiple companies involved in cell therapies. MVM’s interests were reviewed and are managed by Massachusetts General Hospital, and Mass General Brigham in accordance with their conflict-of-interest policies. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
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| معلومات مُعتمدة: | R01 CA238268 United States CA NCI NIH HHS; T32 AI007529 United States AI NIAID NIH HHS; T32 CA009216 United States CA NCI NIH HHS; T32 GM007306 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Cell Engineering; Immunotherapy; Receptors, Chimeric Antigen |
| المشرفين على المادة: | 0 (Receptors, Chimeric Antigen) |
| تواريخ الأحداث: | Date Created: 20240509 Date Completed: 20240509 Latest Revision: 20240605 |
| رمز التحديث: | 20240606 |
| مُعرف محوري في PubMed: | PMC11086422 |
| DOI: | 10.1136/jitc-2023-008417 |
| PMID: | 38724463 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2051-1426 |
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| DOI: | 10.1136/jitc-2023-008417 |