title: Stimulated γδ T cells increase the in vivo efficacy of trastuzumab in HER-2+ breast cancer.
abstract: One fourth of women with HER-2(+) metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human γδ T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20(+) B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated γδ lymphocytes increases the efficacy of trastuzumab against HER-2(+) breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2(+) mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2(+) cells and tumor infiltration by γδ lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant γδ T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated γδ cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2(+) breast cancer.
authors.affiliation: INSERM, Unité Mixte de Recherche 1037, Cancer Research Center of Toulouse, 31024 Toulouse Cedex, France.
authors.forename: Aude-Hélène
authors.initials: AH
authors.lastname: Capietto
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fournié
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D010750:Phosphoproteins / Q000008:administration & dosage / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000008:administration & dosage / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods / Q000473:pathology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006131:Growth Inhibitors; D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000068878:Trastuzumab