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

Rakhshandehroo T., Mantri S. R., Moravej H., Louis B. B. V., Farid A. S., Munaretto L., ...Daha Fazla

NATURE BIOTECHNOLOGY, cilt.43, sa.6, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 43 Sayı: 6
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1038/s41587-024-02339-4
  • Dergi Adı: NATURE BIOTECHNOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Compendex, EMBASE, Environment Index, MEDLINE, Public Affairs Index, Nature Index
  • İstanbul Üniversitesi Adresli: Hayır

Özet

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. Chimeric antigen receptor T cell efficacy is enhanced with an interleukin 2-recruiting molecule.