A CAR enhancer increases the activity and persistence of CAR T cells.

Autor: Rakhshandehroo T; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Mantri SR; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Moravej H; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Louis BBV; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Salehi Farid A; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Munaretto L; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Regan K; Department of Biomedical Engineering, Boston University, Boston, MA, USA., Khan RMM; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Wolff A; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Farkash Z; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Cong M; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Kuhnast A; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Nili A; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Lee UJ; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Allen HH; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Berland L; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Simkova E; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Uslu SC; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Tavakolpour S; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Rowley JE; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biomedical Engineering, Boston University, Boston, MA, USA., Codet E; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Shahbazian H; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Baral J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Pyrdol J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Jacobson CA; Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Nadeem O; Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Nia HT; Department of Biomedical Engineering, Boston University, Boston, MA, USA., Wucherpfennig KW; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Rashidian M; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Mohammad_rashidian@dfci.harvard.edu.; Harvard Medical School, Boston, MA, USA. Mohammad_rashidian@dfci.harvard.edu.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Mohammad_rashidian@dfci.harvard.edu.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Mohammad_rashidian@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Jul 30. Date of Electronic Publication: 2024 Jul 30.
DOI: 10.1038/s41587-024-02339-4
Abstrakt: Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen-CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
Externí odkaz: