To support anti-BCMA CAR T cell persistence, Rakhshandehroo et al. generated an antigen- targeted “CAR enhancer” (CAR-E) by fusing BCMA to a low-affinity IL-2 molecule. In vitro, CAR-E was slowly internalized by CAR T cells and led to their activation (CD69 and pSTAT5). In a mouse tumor model, injecting CAR-E following CAR T improved CAR T expansion, persistence, and memory cell formation, enabling tumor clearance at a sub-curative cell dose. CAR-E supported CAR T protection against tumor rechallenge, and also expanded CAR T cells in the absence of tumor antigen. Engagement of both the IL-2 receptor and CAR molecule was necessary for CAR-E function.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Bos
Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Biomedical Engineering, Boston University, Boston, MA, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (14) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biomedical Engineering, Boston University, Boston, MA, USA. (21) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (24) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Department of Biomedical Engineering, Boston University, Boston, MA, USA. (28) 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. (29) 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.
