Engineering strategies to mitigate toxicities associated with CAR-T cell therapy

Chimeric antigen receptor (CAR) T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy. Owing to the unprecedented efficacy seen in the treatment of blood cancers, the FDA has now approved multiple CAR T cell products for the treatment of various hematologic malignancies. Despite the clinical success seen in hematologic malignancies, CAR T cell therapies have demonstrated only modest efficacy in the treatment of solid tumors. Thus, great efforts are underway to increase the treatment efficacy in solid tumors and further enhance the treatment of hematologic malignancies. However, irrespective of advancements in efficacy, there are still unmet needs for patients receiving CAR T cell therapies. CAR T cell therapies carry significant risks of potentially fatal toxicities, and few of these toxicities were predicted in the animal models used to advance these therapies to the clinic. Therefore, significant advancements are needed to help reduce the incidence and severity of these toxicities to ultimately enhance patient safety and quality of life. This review will provide a brief overview of some of the major toxicities associated with CAR T cell therapies and will discuss the various engineering strategies used to mitigate such toxicities in preclinical models and clinical studies. This review provides a brief overview of several of the major, and potentially life-threatening, toxicities associated with CAR T cell therapies and discusses various examples of the genetic and chemical engineering strategies employed to effectively mitigate such toxicities in preclinical models and clinical studies. image