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.
Keywords: adoptive immunotherapy; cytokine release syndrome; neurotoxicity.
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