title: T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells.
abstract: The adoptive transfer of T cells expressing anti-CD19 chimeric antigen receptors (CARs) has shown remarkable curative potential against advanced B-cell malignancies, but multiple trials have also reported patient relapses due to the emergence of CD19-negative leukemic cells. Here, we report the design and optimization of single-chain, bispecific CARs that trigger robust cytotoxicity against target cells expressing either CD19 or CD20, two clinically validated targets for B-cell malignancies. We determined the structural parameters required for efficient dual-antigen recognition, and we demonstrate that optimized bispecific CARs can control both wild-type B-cell lymphoma and CD19(-) mutants with equal efficiency in vivo To our knowledge, this is the first bispecific CAR capable of preventing antigen escape by performing true OR-gate signal computation on a clinically relevant pair of tumor-associated antigens. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity. Cancer Immunol Res; 4(6); 498-508. ©2016 AACR
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Zah
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California.
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington. Department of Oncology and Hematology, St. Luke's Regional Cancer Center, Duluth, Minnesota.
authors.forename: Anne
authors.initials: A
authors.lastname: Silva-Benedict
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington. Division of Pediatric Hematology-Oncology, University of Washington School of Medicine, Seattle, Washington. Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California. yvonne.chen@ucla.edu.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Chen
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology*; D018951:Antigens, CD20 / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D020014:K562 Cells; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D018951:Antigens, CD20; C000604811:CD19 molecule, human; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins