title: At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies.
abstract: 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.
authors.affiliation: Hematology Oncology Division, Vanderbilt University Medical Center, Nashville, Tennessee, USA; and.
authors.forename: Olalekan O
authors.initials: OO
authors.lastname: Oluwole
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA marco.davila@moffitt.org.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Davila
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D058990:Molecular Targeted Therapy; D015337:Multicenter Studies as Topic; D000072417:Protein Domains; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology*; D013577:Syndrome; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D057170:Translational Research, Biomedical
chemical_list: D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies
keywords: adoptive immunotherapy; cytokine release syndrome; neurotoxicity