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

Abstract T cells expressing chimeric antigen receptors (CARs) have achieved major clinical success in patients with hematologic malignancies. However, these treatments remain largely ineffective for solid cancers and require significant time and resources to be manufactured in an autologous setting. Developing alternative immune effector cells as cancer immunotherapy agents that can be employed in allogeneic settings is crucial for the advancement of cell therapy. 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, transactivate NK cells, and cross-prime tumor-specific CD8 T cells. Both unmodified NKTs, which specifically recognize CD1d-bound glycolipid antigens expressed by certain types of tumors, and CAR-redirected NKTs are being developed 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 the clinical experiences of unmodified and CAR-redirected NKTs, including recent interim reports on allogeneic NKTs.