NKT cells as a novel platform for cancer immunotherapy with chimeric antigen receptors (P2038)

Abstract

Abstract Transgenic expression of chimeric antigen receptors (CARs) in primary T cells is an attractive strategy for cancer immunotherapy. However, poor homing of CAR T cells to the tumor site limits their therapeutic potential. Because Vα24-invariant Natural Killer T cells (NKTs) naturally localize to solid tumors, we examined their ability to serve as a cellular carrier for anti-tumor CARs. We genetically modified primary human NKTs to express a CAR against GD2 ganglioside, which is highly expressed in tumors of neuroectodermal origin such as neuroblastoma or melanoma. CAR expression rendered NKTs highly cytotoxic against GD2-positive neuroblastoma cells without affecting their native CD1d-restricted reactivity. The comparison of CAR constructs encoding different co-stimulatory endodomains revealed a striking Th2-like or Th1-like polarization of NKTs by CARs with CD28 or CD137, respectively. CAR NKTs had potent and long-lasting anti-tumor activity in a metastatic model of neuroblastoma in humanized NOD/SCID/IL-2γ(null) mice. Furthermore, in contrast to CAR T cells from the same donor, CAR NKTs did not induce graft-versus-host disease. These results establish the potential of NKTs to serve as an effective cellular platform for anti-tumor CAR therapy.