Synthetic T cell receptor-based lymphocytes for cancer therapy

Chimeric antigen receptor (CAR) T cells have been remarkably successful in patients with hematological malignancies expressing the CD19 surface antigen, but such level of success is far from being replicated in solid tumors. Engineered T cell receptor (TCR) T cells targeting cancer antigens were first developed over two decades ago and represent an alternative adoptive T cell approach that has produced provocative clinical data in solid cancers. However, several factors may hinder this technology from realizing its full potential, including the need for HLA matching, HLA downregulation by cancer cells, the suppressive tumor microenvironment, and tissue liabilities resulting from targeting antigens shared with normal tissues. Efforts therefore continue to engineer enhanced versions of CAR T and TCR T therapies that can overcome current barriers. Furthermore, emergent novel TCR-based, HLA-unrestricted platforms may also provide unique tools that integrate the complexity of the TCR signaling cascade that can be applied to treat solid tumors. This article reviews the current state of development of TCR T cell approaches and discusses next generation improvements to overcome their current limitations.