Abstract B08: Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors

Advances in the design of chimeric antigen receptors (CARs) have improved the anti-tumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells and their restriction by polymorphic HLA molecules limit their therapeutic potential and are associated with toxicity, especially in allogeneic settings. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) can build upon the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKTs were engineered to express a CAR against the GD2 ganglioside, which is highly expressed by neuroblastoma. We compared CAR constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB co-stimulatory endodomains. CAR expression rendered NKTs highly cytotoxic against neuroblastoma cells without affecting their TCR-induced proliferation and CD1d-dependent killing of M2-polarized macrophages. We observed a striking Th1-like polarization of NKTs by 4-1BB-containing CARs in vitro and in mice. Expression of both CD28 and 4-1BB endodomains in the CAR maximized persistence of NKTs in NSG mice with neuroblastoma xenografts. These NKTs, expressing CAR with two co-stimulatory endodomains localized to the tumor site more effectively than T cells with the same CAR (p Citation Format: Andras Heczey, Daofeng Liu, Gengwen Tian, Ekaterina Marinova, Xiuhua Gao, Linjie Guo, John Hicks, Gianpietro Dotti, Leonid Metelitsa. Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B08.