Combining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma

  • Leukemia. 2025 Jul 30. doi: 10.1038/s41375-025-02697-1.
Tayla B Heavican-Foral  1  2  3 ,  Felix Korell  4 ,  Irene Scarfò  4  5 ,  Caroline R M Wiggers  1  3 ,  Allen Thayakumar B  1  2 ,  Zachary Eisenbies  1 ,  Foster Powers  2 ,  Justin Hegel  1 ,  Jianlin Liu  1  6 ,  Steffen Kulp  2 ,  Harrison Silva  4 ,  Gongwei Wu  2  3 ,  Anthony Letai  2  3 ,  Kimberly Stegmaier  1  3 ,  Jens G Lohr  2  3  6 ,  David M Weinstock  2  3  7 ,  Marcela V Maus  #  8  9 ,  Birgit Knoechel  #  10  11  12
Affiliations
  • 1. Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3. Harvard Medical School, Boston, MA, USA.
  • 4. Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
  • 5. ArsenalBio, South San Francisco, CA, USA.
  • 6. Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • 7. Merck Research Laboratories, Boston, MA, USA.
  • 8. Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. [email protected].
  • 10. Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 11. Harvard Medical School, Boston, MA, USA. [email protected].
  • 12. Huntsman Cancer Institute, Salt Lake City, UT, USA. [email protected].
  • # Contributed equally.
PMID: 40739330 DOI: 10.1038/s41375-025-02697-1
Abstract

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 and prolongs survival of xenografted mice. These findings suggest that personalized selection of BH3 mimetic/CAR-T combinations could maximize the therapeutic index for patients with TCL and possibly Other Diseases.

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