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

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...

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Bibliographic Details
Published in:Leukemia 2024-03, Vol.38 (3), p.590-600
Main Authors: Kann, Michael C., Schneider, Emily M., Almazan, Antonio J., Lane, Isabel C., Bouffard, Amanda A., Supper, Valentina M., Takei, Hana N., Tepper, Alexander, Leick, Mark B., Larson, Rebecca C., Ebert, Benjamin L., Maus, Marcela V., Jan, Max
Format: Article
Language:English
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Antigens
Cancer
Cancer Research
Cell Line, Tumor
Cell therapy
Cells
Cloning
Critical Care Medicine
Cytokines
Cytokines - metabolism
Degradation
Flow cytometry
Fusion protein
Genetic control
Hematology
Humans
Immunotherapy
Immunotherapy, Adoptive
Intensive
Interleukin 7
Interleukin-7 - metabolism
Internal Medicine
Lenalidomide - pharmacology
Leukemia
Lymphocytes
Lymphocytes T
Malignancy
Medicine
Medicine & Public Health
Membrane fusion
Membranes
Oncology
Phenotypes
Proteins
Receptors, Antigen, T-Cell - genetics
T-Lymphocytes - metabolism
Targeted cancer therapy
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Summary: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.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-023-02113-6