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

In a collaborative study, researchers from the Dana-Farber Cancer Institute and Harvard Medical School, have developed a new strategy to enhance the activity and persistence of chimeric antigen receptor (CAR T) cells using a novel CAR enhancer (CAR-E). This enhancer is comprised of a CAR T-cell antigen fused to a low-affinity interleukin-2 (IL-2) molecule, designed to selectively activate CAR T cells upon antigen binding while reducing IL-2-associated toxicities. In preclinical models targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) treatment, the CAR-E significantly boosted CAR T-cell proliferation, increased tumor clearance, and promoted the development of long-lasting memory CAR T cells.

Limitations of current CAR T-cell therapies, particularly the rapid loss of CAR T cells after infusion which often leads to disease relapse within a year, presented an unmet medical need. Therefore, the researchers sought a solution that would improve CAR T-cell persistence without the need for complex genetic modifications. The novel CAR-E was created by fusing a BCMA antigen with a low-affinity mutant human IL-2 dimer (mutIL-2), allowing selective stimulation of CAR T cells upon antigen recognition. This approach aims to prolong CAR T-cell activity and improve patient outcomes.

Overall, the CAR-E enhanced the persistence of CAR T cells in vivo and increased their tumor-killing efficacy without inhibiting their function. In mouse models of MM, a single dose of CAR-E led to a significant reduction in tumor cells and long-term control of tumor growth. Flow cytometry analyses showed a robust expansion of memory CAR T cells in treated mice, and these cells retained their ability to re-expand upon re-challenge. This strategy represents a major advancement in CAR T-cell therapy, offering a more durable and effective treatment for patients with hematologic malignancies. Further clinical studies will be needed to confirm these findings in human clinical trials.

Reference:

Rakhshandehroo T, Mantri SR, Moravej H, et al. A CAR enhancer increases the activity and persistence of CAR T cells. Nat Biotechnol. Published online July 30, 2024. http://doi.org/10.1038/s41587-024-02339-4