Targeting T-Cells for Cancer Treatment: Current Clinical Strategies and Challenges.

Modulation of immune response to target tumor cells has been shown to be a successful strategy for cancer treatment. Over the past years immunotherapy has been integrated into cancer treatment and PD-1 blockers have become the backbone of treatment regimens for multiple cancer types. Several classes of immunotherapies, such as immune checkpoint blockers, bispecific antibodies, chimeric antigen receptor (CAR) T-cells, and tumor-infiltrating lymphocytes (TILs), were approved by the US FDA in the last decade and many more are in clinical trials. Research on redirecting effector T-cells to treat cancer has been aimed at addressing the limited responses in solid tumors, emergence of resistance, treatment-limiting adverse events and logistical challenges. Bispecific immune checkpoint blockers, developed to simplify the combination therapies; bispecific T-cell engagers, developed to connect the effector T-cells with tumor cells; and the next generation of CAR T-cells and the next generation of TIL therapies, developed to improve efficacy in solid tumors, are currently under clinical evaluation. This narrative review aims to summarize the current status of T-cell-directed immunotherapy, describing the brief history of development, clinical success, challenges and latest advancements that are under clinical evaluation. Evolution of monoclonal antibodies to bispecific antibodies and bispecific T-cell engagers, the latest advances in adoptive cell therapies, including the optimization of CAR T-cells for solid tumors, allogenic, universal CAR T-cells and in vivo CAR T-cell therapies are discussed in the review along with the key challenges of the therapies, such as primary and acquired resistance, limited efficacy in solid tumors, manufacturing and logistical challenges, and treatment-related toxicities.