Natural killer T cells and other innate-like T lymphocytes as emerging platforms for allogeneic cancer cell therapy.

T cells expressing chimeric antigen receptors (CARs) have achieved major clinical successes in patients with hematologic malignancies. However, these treatments remain largely ineffective in solid cancers and require significant time and resources to manufacture in the autologous setting. Developing alternative immune effector cells as cancer immunotherapy agents that can be employed in the allogeneic setting is crucial for advancement of the cell therapy field. Unlike T cells, Vα24-invariant natural killer T cells (NKTs) are not alloreactive and can therefore be generated from allogeneic donors for rapid infusion into numerous patients without the risk of graft-versus-host disease. Additionally, NKT cells demonstrate inherent advantages over T cell products including the ability to traffic to tumor tissues, target tumor-associated macrophages, trans-activate NK cells, and cross-prime tumor-specific CD8 T cells. Both unmodified NKTs, which specifically recognize CD1d-bound glycolipid antigens expressed by some types of tumors, and CAR-redirected NKTs are in development as the next generation of allogeneic cell therapy products. In this review, we describe studies on the biology of NKTs and other types of innate-like T cells and summarize experiences in the clinic with unmodified and CAR-redirected NKTs, including recent interim reports on allogeneic NKTs.