title: Bromohydrin pyrophosphate-stimulated Vgamma9delta2 T cells expanded ex vivo from patients with poor-prognosis neuroblastoma lyse autologous primary tumor cells.
abstract: Gamma/delta T cells (Vgamma9delta2) contribute to innate immunity and exert natural cytotoxicity against a variety of tumors. Using a synthetic phosphoantigen (Bromohydrin Pyrophosphate, BrHPP), we amplified Vgamma9delta2 T cells in vitro from neuroblastoma patients. In the presence of BrHPP and low doses of IL-2, robust proliferation of Vgamma9delta2 T cells was obtained from peripheral blood mononuclear cells (PBMC) harvested at diagnosis. Moderate proliferation was observed from PBMC harvested after stem cell transplantation, whereas modest levels of Vgamma9delta2 T cells were obtained from PBMC harvested after induction therapy. Proliferation was observed after a single in vitro stimulation with BrHPP. After 21 days in culture, Vgamma9delta2 T cells represented more than 80% of cultured cells (a 50-fold expansion from baseline). Moreover, BrHPP-amplified Vgamma9delta2 T cells from patients-expressed activation markers and were able to lyse allogeneic and autologous neuroblasts. This cytotoxic activity was gammadelta T-cell receptor-dependent. Clinical trials using BrHPP are warranted in patients with poor-prognosis neuroblastoma, either to expand patient-derived Vgamma9delta2 T cells ex vivo or by direct administration to in vivo to boost the pool of resident Vgamma9delta2 T cells in vivo.
authors.affiliation: Innate Pharma, 117, Bld de Luminy, Marseille, France. jamel.chargui@innate-pharma.fr
authors.forename: Jamel
authors.initials: J
authors.lastname: Chargui
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Virginie
authors.initials: V
authors.lastname: Scaglione
authors.forename: Isabelle
authors.initials: I
authors.lastname: Iacono
authors.forename: Valentine
authors.initials: V
authors.lastname: Péri
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Marie
authors.initials: M
authors.lastname: Dubrel
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.forename: François
authors.initials: F
authors.lastname: Romagne
authors.forename: Christophe
authors.initials: C
authors.lastname: Bergeron
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D011756:Diphosphates / Q000276:immunology*; D018450:Disease Progression; D006801:Humans; D008213:Lymphocyte Activation; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D011379:Prognosis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D011756:Diphosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C429553:bromohydrin pyrophosphate