Chimeric Antigen Receptor T Cells for Cancer Immunotherapy

T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). The clinical benefit of CAR T cells has now been reported by several groups targeting the CD19 antigen in patients with hematologic malignancies. However, in solid tumors, CAR T cells have been less effective at inducing complete tumor responses and have mediated a high rate of on-target/ off-tumor toxicity. To understand this discrepancy, we must understand the design and implementation of CAR T cells for cancer immunotherapy. The basic design of CAR T cells consists of two fundamental domains: the antigen-binding portion (commonly composed of a single-chain variable fragment [scFv] derived from a monoclonal antibody [mAb]) joined to one or more intracellular T-cell signaling domains. To be effective after infusion, CAR T cells must expand, persist, exhibit enduring antitumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal CAR T cell.