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IMMUNOTHERAPY

Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7

Leukemia volume 38, pages 590–600 (2024)Cite this article

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Abstract

CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.

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Fig. 1: mbdIL-7 endows CAR-T cells with superior in vivo tumor control.
Fig. 2: mbdIL-7 degradation activity is robust and reversible in vitro and in vivo controlling both surface IL-7 and pSTAT5 signaling.
Fig. 3: mbdIL-7 CAR have less differentiated product phenotype and maintain short-term in vitro activity to standard CAR-T cells.
Fig. 4: CAR19 mbdIL-7 have superior long-term proliferation potential.
Fig. 5: mbdIL-7 OFF-activity controls unchecked T cell expansion.

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Data availability

For original data, please contact mvmaus@mgh.harvard.edu.

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Acknowledgements

This work was supported by R01CA238268 to MVM and NIH K08CA255932, Leukemia Research Foundation New Investigator Award, Damon Runyon Cancer Research Foundation Innovator Award, American Cancer Society Discovery Boost Grant, and Edward P. Evans Foundation Discovery Research Grant to MJ. Select figures created with BioRender.com.

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Authors and Affiliations

  1. Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    Michael C. Kann, Emily M. Schneider, Antonio J. Almazan, Isabel C. Lane, Amanda A. Bouffard, Valentina M. Supper, Hana N. Takei, Mark B. Leick, Rebecca C. Larson, Marcela V. Maus & Max Jan

  2. Harvard Medical School, Boston, MA, USA

    Emily M. Schneider, Mark B. Leick, Rebecca C. Larson, Marcela V. Maus & Max Jan

  3. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA

    Emily M. Schneider

  4. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Alexander Tepper, Benjamin L. Ebert, Marcela V. Maus & Max Jan

  5. Blood and Bone Marrow Transplant Program, Massachusetts General Hospital, Boston, MA, USA

    Mark B. Leick

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Benjamin L. Ebert

  7. Howard Hughes Medical Institute, Bethesda, MD, USA

    Benjamin L. Ebert

  8. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Max Jan

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Contributions

MCK, EMS, AJA, ICL, AAB, VMS, HNT, AT, and MJ performed the experiments; MCK and MJ analyzed the results and created the figures; RCL, MBL, and BLE provided critical expertise in immune-oncology and targeted protein degradation; MCK, MVM, and MJ designed the study; MCK, MVM, and MJ wrote the manuscript; and all other authors read, edited, and approved the final version of this manuscript.

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Correspondence to Marcela V. Maus.

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Competing interests

MCK, MVM, and MJ are listed as inventors on patents related to this work and held by the Massachusetts General Hospital and Partners Health Care. BLE has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. MVM is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). MVM holds equity in 2SeventyBio, Century Therapeutics, Genocea, Neximmune, Oncternal, and TCR2 and has served as a consultant for multiple companies involved in cell therapies. MJ has received consulting income from RA Ventures. MJ is an inventor on patents related to molecular switch control of genetically engineered immune effector cell therapies held by Mass General Brigham and the Broad Institute.

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Kann, M.C., Schneider, E.M., Almazan, A.J. et al. Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7. Leukemia 38, 590–600 (2024). https://doi.org/10.1038/s41375-023-02113-6

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