262 Multiple targeting of solid tumors with iPSC-derived gamma delta CAR T cells in combination with therapeutic antibodies

Abstract

Background CAR-T cell therapies have proven safe and effica-cious for hematologic malignancies, but there remains a signif-icant unmet need for effective cell therapy options for solid tumors. CAR-engineered induced pluripotent stem cell (iPSC)-derived effector cells allow for the treatment of cancer as an off-the-shelf allogeneic cell therapy. Gamma delta ( gd ) T cells exhibit the cytolytic features of conventional alpha beta ( ab ) CD8 + T cells with additional capabilities for innate recognition of tumors. For example, expression of CD16 on gd T cells can mediate antibody-dependent cellular cytotoxicity (ADCC) against tumors. Here we describe development of an iPSC-derived CAR gd T cell platform which can target solid tumors through both CAR-mediated recognition and ADCC when combined with a therapeutic antibody. process yielding >90% pure CAR + gd T cells. The TiPSCs contained the rearranged gd TCR gene and upon differentiation to T cells, uniformly expressed a V g 9V d 2 TCR and expressed high levels of CD16. CAR gd T cells were effective in killing SKOV-3 spheroids. When cultured with SKOV-3 spheroids in an ADCC assay, CAR gd T cells exhibited enhanced cytotoxicity in the presence of trastuzumab but not isotype control antibody. Activity of the gd T cells was not reliant on additional exogenous cytokine due to the engineered form of membrane-associated IL-15. Conclusions We have demonstrated that iPSC-derived gd T cells mediate anti-tumor activity in human solid tumor models through multiple pathways. The combination of two modes of tumor recognition (CAR and CD16/antibody) enabled more potent killing of solid tumor spheroids. The ability to manu-facture large batches of iPSC derived CAR gd T cells will enable a true off-the-shelf allogenic cell therapy for solid tumors.