CAR T cell preconditioning with IL-15 augments stem cell qualities and checkpoint blockade responsiveness for improved treatment of solid tumors

Abstract Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their 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 PD-1 blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and IL-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whilst 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 preconditioning 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 indicates 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.