Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15

Purpose: A delay in encountering the cognate antigen while in the circulation, and the suboptimal costimulation received at the tumor site are key reasons for the limited activity of chimeric antigen receptor-redirected T cells (CAR-Ts) in solid tumors. We have explored the benefits of incorporating the interleukin (IL)-15 cytokine within the CAR cassette to provide both a survival signal before antigen encounter, and an additional cytokine signaling at the tumor site using a neuroblastoma (NB) tumor model. Experimental design: We optimized the construct for the CAR specific for the NB-antigen GD2 without (GD2.CAR) or with IL-15 (GD2.CAR.15). We then compared the expansion, phenotype and antitumor activity of T cells transduced with these constructs against an array of NB cell lines in vitro and in vivo using a xenogeneic metastatic model of NB. Results: We observed that optimized GD2.CAR.15-Ts have reduced expression of the PD-1 receptor, are enriched in stem-cell like cells, and have superior antitumor activity upon repetitive tumor exposures in vitro and in vivo as compared to GD2.CAR-Ts. Tumor re-challenge experiments in vivo further highlighted the role of IL-15 in promoting enhanced CAR-Ts antitumor activity and survival, both in the peripheral blood and tissues. Finally, the inclusion of the inducible caspase-9 gene (iC9) safety switch warranted effective on demand elimination of the engineered GD2.CAR.15-Ts. Conclusion: Our results guide new therapeutic options for GD2.CAR-Ts in patients with NB, and CAR-T development for a broad range of solid tumors.

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