Neutralization of murine myeloid suppressor cells enhances the efficacy of GD2-specific CAR T cells directed against human sarcoma in a xenograft model (VAC11P.1010)

Genetically engineered T-cells expressing chimeric antigen receptors directly target cell surface antigens on tumor cells. CARs have shown remarkable activity in clinical trials for hematologic malignancies but remain unproven for the treatment of solid tumors. The disialoganglioside GD2 is considered a tumor-associated antigen for neuroblastoma and we have found that GD2 is expressed on pediatric sarcomas. Analysis of primary human tumor tissue samples taken from 18/18 patients with osteosarcoma and alveolar rhabdomyosarcoma (2/15) demonstrate robust expression of GD2 on the cell surface. Based on this finding, we developed assays to test the ability of GD2-CAR T-cells to target human sarcomas. We find that GD2-CAR T-cells specifically lyse GD2-expressing solid tumors in vitro even at low E:T, but fail to induce a response in vivo. In studying these xenografted tumors we discovered an expansion of murine CD11b+Gr1+ MDSC that inhibit human T-cell responses in vitro. This lead us to adopt a combinatorial therapeutic strategy in which we inhibited the suppressive potential of MDSC by administration of all-trans retinoic acid followed by the infusion of GD2-specific CAR T-cells. This resulted in significant improvements in overall survival and tumor growth. The results presented here suggest that ATRA coadministration with CAR T-cell therapy for solid tumors may yield a beneficial additive effect through the modulation of myeloid derived suppressor cells.