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

Nat Biotechnol. 2025 Jun;43(6):948-959. doi: 10.1038/s41587-024-02339-4. Epub 2024 Jul 30.

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.

MeSH terms

  • Animals
  • B-Cell Maturation Antigen / genetics
  • B-Cell Maturation Antigen / immunology
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Mice
  • Multiple Myeloma* / immunology
  • Multiple Myeloma* / therapy
  • Receptors, Antigen, T-Cell* / immunology
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / metabolism
  • T-Lymphocytes* / immunology

Substances

  • Receptors, Chimeric Antigen
  • Interleukin-2
  • B-Cell Maturation Antigen
  • Receptors, Antigen, T-Cell