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

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

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. mvmaus@mgh.harvard.edu.
  • 9 Cancer Center, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu.
  • 10 Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. birgit_knoechel@dfci.harvard.edu.
  • 11 Harvard Medical School, Boston, MA, USA. birgit_knoechel@dfci.harvard.edu.
  • 12 Huntsman Cancer Institute, Salt Lake City, UT, USA. birgit_knoechel@dfci.harvard.edu.
  • # 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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