title: Novel approaches to enhance the specificity and safety of engineered T cells.
abstract: T-cell therapies using engineered T cells show great promise for cancer immunotherapy, as illustrated by the CD19 paradigm. Much of the excitement about this approach, and second-generation CARs in particular, is due to the dramatic clinical results recently reported by a few centers, especially in acute lymphoblastic leukemia, and the applicability of this approach, in principle, to a wide range of cancers. Extending the use of CAR therapies to cancers other than B-cell malignancies will require selective tumor targeting with minimal or acceptable "on-target, off-tumor" effects. The identification of new CAR target antigens is thus one of the next big challenges to address. Recognizing the paucity of currently available tumor-specific targets, we have developed broadly applicable approaches to enhance the tumor selectivity and safety of engineered T cells. Here, we review 2 promising concepts. One is to improve tumor targeting based on combinatorial antigen recognition. The other uses receptors that provide antigen-specific inhibition, which we named iCARs, to divert T cells from the normal tissues one wants to protect.
authors.affiliation: From the *Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY; †Tri-Institutional MSTP Program (MSKCC, Rockefeller University, Weill-Cornell Medical College), New York, NY; ‡Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY; and §Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Ave, New York, NY.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Fedorov
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Kloss
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D000939:Epitopes; D006801:Humans; D016219:Immunotherapy, Adoptive; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000939:Epitopes; D011948:Receptors, Antigen, T-Cell