At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies
T cells kill microbial infected and malignant cells by detection of nonself antigens with the TCR. Tumor reactivity can be encoded genetically by introducing a chimeric antigen receptor (CAR) into T cells. CARs are composed of an antigen binding domain and an intracellular T cell activation domain. Early human trials evaluating CD19 targeted CAR T cells for chronic lymphocytic leukemia (CLL) showed limited responses until CARs included a costimulation domain, and conditioning chemotherapy was given before T cell infusion. Clinical trials evaluating CD19 targeted CAR T cells for B cell acute lymphoblastic leukemia (B ALL) are demonstrating response rates up to 90% However, these clinical outcomes are associated with a cytokine release syndrome (CRS) which is caused by T cell activation and manifests as high grade fever, hypotension, and other cardiovascular complications. It is currently managed conservatively but can be treated with cytokine directed therapy or with high dose steroids. Current efforts are dedicated to confirming the clinical efficacy and managing toxicities in multicenter Phase II trials. We present a thorough overview of the preclinical and clinical development of CAR T cell therapy that will highlight important areas for the basic researcher to investigate in the laboratory and contribute to this exciting field.
Journal of leukocyte biology