title: Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy.
abstract: A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated.
authors.affiliation: Laboratory of Immunology, MIGAL, Galilee Research Institute, Kiryat Shmona 11016, Israel; email: gidi@migal.org.il.|Department of Biotechnology, Tel-Hai College, Upper Galilee 12210, Israel.|Center of Cancer Research, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Gross
authors.affiliation: Center of Cancer Research, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.|Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; email: zelig.eshhar@weizmann.ac.il.
authors.forename: Zelig
authors.initials: Z
authors.lastname: Eshhar
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins
keywords: CARs; adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptors; on/off-target effects; tumor antigens