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  • IL-15 Preconditioning Augme...
    Giuffrida, Lauren; Sek, Kevin; Henderson, Melissa A.; House, Imran G.; Lai, Junyun; Chen, Amanda X.Y.; Todd, Kirsten L.; Petley, Emma V.; Mardiana, Sherly; Todorovski, Izabela; Gruber, Emily; Kelly, Madison J.; Solomon, Benjamin J.; Vervoort, Stephin J.; Johnstone, Ricky W.; Parish, Ian A.; Neeson, Paul J.; Kats, Lev M.; Darcy, Phillip K.; Beavis, Paul A.

    Molecular therapy, 11/2020, Letnik: 28, Številka: 11
    Journal Article

    Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4– population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols. Display omitted