title: DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma.
abstract: Chimeric antigen receptor (CAR) T cell therapies hold great potential for treating cancers, and new CARs that can target multiple tumor types and have the potential to target non-hematological malignancies are needed. In this study, the tumor recognition ability of a natural killer cell-activating receptor, DNAM-1 was harnessed to design CARs that target multiple tumor types. DNAM-1 ligands, PVR and nectin-2, are expressed on primary human leukemia, myeloma, ovarian cancer, melanoma, neuroblastoma, and Ewing sarcoma. DNAM-1 CARs exhibit high tumor cell cytotoxicity but low IFN-γ secretion in vitro. In contrast to other CAR designs, co-stimulatory domains did not improve the expression and function of DNAM-1 CARs. A DNAM-1/CD3zeta CAR reduced tumor burden in a murine melanoma model in vivo. In conclusion, DNAM-1-based CARs may have the potential to treat PVR and nectin-2 expressing hematological and solid tumors.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Ming-Ru
authors.initials: MR
authors.lastname: Wu
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Andre
authors.initials: A
authors.lastname: Alcon
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell