title: NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors.
abstract: Tumor heterogeneity presents a substantial barrier to increasing clinical responses mediated by targeted therapies. Broadening the immune response elicited by treatments that target a single antigen is necessary for the elimination of tumor variants that fail to express the targeted antigen. In this study, it is shown that adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) inhibited the growth of target-expressing and -deficient tumor cells within ovarian and lymphoma tumors. Mice bearing the ID8 ovarian or RMA lymphoma tumors were treated with T cells transduced with a NKG2D-based CAR (chNKG2D). NKG2D CAR T-cell therapy protected mice from heterogeneous RMA tumors. Moreover, adoptive transfer of chNKG2D T cells mediated tumor protection against highly heterogeneous ovarian tumors in which 50, 20 or only 7% of tumor cells expressed significant amounts of NKG2D ligands. CAR T cells did not mediate an in vivo response against tumor cells that did not express sufficient amounts of NKG2D ligands, and the number of ligand-expressing tumor cells correlated with therapeutic efficacy. In addition, tumor-free surviving mice were protected against a tumor re-challenge with NKG2D ligand-negative ovarian tumor cells. These data indicate that NKG2D CAR T-cell treatment can be an effective therapy against heterogeneous tumors and induce tumor-specific immunity against ligand-deficient tumor cells.
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Spear
authors.forename: Amorette
authors.initials: A
authors.lastname: Barber
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rynda-Apple
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000637:transplantation; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma