Abstract
Limited CAR T-cell expansion and persistence hinder therapeutic responses in solid cancer patients. To enhance the functional persistence of engineered T-cell therapies, we performed genetic disruption in human CAR T cells of SUV39H1, a histone 3 lysine 9 methyltransferase that promotes heterochromatin formation. This resulted in phenotypic CAR-T reprogramming that elicited optimal and sustained antitumor functionality. Single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses of tumor-infiltrating CAR T cells showed early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all subpopulations. Moreover, we provided evidence that SUV39H1 inactivation elicits potent and durable functional persistence upon multiple tumor rechallenges. This opens a safe path to enhancing adoptive cell therapies for solid tumors.
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All contributions were from MS.
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MS is an employee of Mnemo Therapeutics and has patents NZ784223A, 6AU2020318781A1, CA3146895A1, BR112022001148A2, CN114222815A, KR1020220042161A, EP4003407A1, IL290020A, US20220251572A1, JP2022542102A, ID202204093A, IN202217002911A, ZA202200961A, MX2022000922A, SG11202200326WA, and HK40066314A pending and licensed to Mnemo Therapeutics and a patent for PCT EP2023/063702 pending.
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Saitakis, M. Epigenetic reprogramming of CAR T cells for in vivo functional persistence against solid tumors. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00262-x
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DOI: https://doi.org/10.1038/s41435-024-00262-x