biostudies-literatureHeavican-Foral TBNCI NIH HHS2452-2464https://www.ebi.ac.uk/biostudies/studies/S-EPMC12463675biostudies-literatureUnknown39(10)Chimeric antigen receptor (CAR) T cell therapy has not yet been realized for T-cell lymphomas (TCL), partially due to challenges in identifying tumor-specific antigens. We previously reported selective expression of CD37 on malignant T cells in a subset of TCL. Herein, we demonstrate CAR-37 T cells specifically target CD37-positive TCL in part by activating the intrinsic apoptotic pathway. To maximize therapeutic index, we identified selective/targetable BH3 dependences in individual TCL models and combined with CAR-37 T cells. We show that BH3 mimetics do not alter CD37 antigen binding capacity on TCL and have minimal effects on CAR-37 T-cell phenotype or function. In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response LeukemiaCombining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma.PMC12463675R01 CA249185R01 CA249062R35 CA231958R35 CA210030P01 CA233412Stegmaier KLohr JGLiu JLetai AWiggers CRMKorell FWu GHegel JWeinstock DMB ATEisenbies ZSilva HPowers FScarfo IHeavican-Foral TBKnoechel BMaus MVKulp SfalseCombining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma.Chimeric antigen receptor (CAR) T cell therapy has not yet been realized for T-cell lymphomas (TCL), partially due to challenges in identifying tumor-specific antigens. We previously reported selective expression of CD37 on malignant T cells in a subset of TCL. Herein, we demonstrate CAR-37 T cells specifically target CD37-positive TCL in part by activating the intrinsic apoptotic pathway. To maximize therapeutic index, we identified selective/targetable BH3 dependences in individual TCL models and combined with CAR-37 T cells. We show that BH3 mimetics do not alter CD37 antigen binding capacity on TCL and have minimal effects on CAR-37 T-cell phenotype or function. In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response 2025-01-01T00:00:00Z2025 Oct2026-07-15T06:51:46.935Z2026-06-30T03:28:12.907ZS-EPMC124636754073933010.1038/s41375-025-02697-1