Regulation of CAR T cell exhaustion and effects of IL-4
Stewart CM, Siegler EL, Sakemura RL, et al. IL-4 Drives Exhaustion of CD8-Positive CART Cells. Nature Communications. 2024; (doi: 10.1038/s41467-024-51978-3).
Researchers say interleukin 4 (IL-4) is implicated in chimeric antigen receptor (CAR) T-cell exhaustion — a primary factor blocking durable response to CAR immunotherapy — and thus may represent a pathway to improved efficacy. Exhaustion is a state of dysfunction caused by chronic stimulation via the T cell receptor in CD8-positive T cells or through the CAR in CAR T cells. Through three independent approaches that used preclinical models and clinical trial samples, scientists determined that IL-4 is an upstream regulator of CAR T-cell dysfunction, including exhaustion. Based on greater production of IL-4 by CD-positive CAR T cells following chronic stimulation and a significant reduction in CD4-positive CAR T cells, they suspect the effect of IL-4 on the CD8-positive population is of greater interest. In xenograft murine models of mantle cell lymphoma, coupling CAR T-cells with an IL-4 monoclonal antibody increased antitumor efficacy and reduced signs of CAR T-cell exhaustion. IL-4 neutralization may prevent CAR T exhaustion and enhance CAR T-cell efficacy, the researchers report.