Giuffrida et al. showed that preconditioning CAR T cells with IL-7/IL-15 (compared to IL-2/IL-7) following transduction enhances their antitumor efficacy when combined with anti-PD-1 therapy. IL-7/IL-15 treatment promoted epigenetic and transcriptional changes in CAR T cells, with increases in central memory (CD62L+CD44+; TCM) and stem cell-like (CD62L+CD44dim; TSCM) gene expression, which are associated with response to immune checkpoint blockade. IL-7/IL-15-treated CD62L+TCF7+ CAR T cells were most responsive to therapy with anti-PD-1, showing increased expression of effector molecules, including IFNγ and TNF.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VI
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (10) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (11) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (12) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (13) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (15) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (18) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Immunology, Monash University, Clayton, VIC 3168, Australia. Electronic address: phil.darcy@petermac.org. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: paul.beavis@petermac.org.
