title: Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies.
abstract: In human blood, 1% to 5% of lymphocytes are gammadelta T cells; they mostly express the gammadelta T-cell receptor (TCR)Vgamma9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by gammadelta T cells is unknown. Here we report that, in association with the CD20(+)-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVgamma9(+) cell binding to CD20(+) lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20(+) cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by gammadelta T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVgamma9(+) lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs.
authors.affiliation: Inserm U, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Gertner-Dardenne
authors.forename: Cecile
authors.initials: C
authors.lastname: Bonnafous
authors.forename: Christine
authors.initials: C
authors.lastname: Bezombes
authors.forename: Aude-Hélène
authors.initials: AH
authors.lastname: Capietto
authors.forename: Virginie
authors.initials: V
authors.lastname: Scaglione
authors.forename: Sophie
authors.initials: S
authors.lastname: Ingoure
authors.forename: Delphine
authors.initials: D
authors.lastname: Cendron
authors.forename: Emilie
authors.initials: E
authors.lastname: Gross
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lepage
authors.forename: Anne
authors.initials: A
authors.lastname: Quillet-Mary
authors.forename: Loîc
authors.initials: L
authors.lastname: Ysebaert
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Hélène
authors.initials: H
authors.lastname: Sicard
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fournié
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D011756:Diphosphates / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D010710:Phosphates / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D000069283:Rituximab; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D011756:Diphosphates; D007376:Interleukin-2; D010710:Phosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; C541125:TCRVgamma9 protein, human; C429553:bromohydrin pyrophosphate; D000069283:Rituximab