Targeting CD37 and BH3 dependencies for T-cell lymphoma CAR-T therapy
Heavican-Foral TB, Korell F, Scarfo I, et al. Combining MCL-1 Inhibition and CD37-Directed Chimeric Antigen Receptor T Cells as an Effective Strategy to Target T-Cell Lymphoma. Leukemia. 2025; (doi: 10.1038/s41375-025-02697-1).
Tumor-specific antigens remain elusive in T-cell lymphomas (TCL), effectively limiting the impact of chimeric antigen receptor (CAR) T-cell therapy in this setting, but scientists are encouraged by the potential of CD37 T cells working in tandem with the MCL-1 inhibitor AZD5991. Preclinical work indicates that CAR-37 T cells exhibit robust anti-tumor activity against TCL, and the antigen is expressed almost exclusively on malignant cells and rarely on mature T cells. A less-than-optimal duration of response prompted investigators to explore ways to increase the effect of CAR T-cell activity without sacrificing tolerability. They used BH3 profiling to identify targetable BH3 dependencies in individual TCL models and then coupled them with the CAR-37 T cells. In lymphoma models with dependence on MCL-1, the combination of CAR-37 T cells and AZD5991 enhanced anti-TCL response and kept xenografted mice alive longer. According to researchers, the results suggest that personalized selection of BH3 mimetic/CAR T pairings could boost the therapeutic index of patients with TCL and also possibly for patients with other hematologic malignancies.