title: Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells.
abstract: Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluatedin vitrocytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expandedin vitrowith zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.
authors.affiliation: University College London Institute of Child Health; Developmental Biology and Cancer Section ; London, UK.
authors.forename: Jonathan P H
authors.initials: JP
authors.lastname: Fisher
authors.affiliation: University College London Institute of Child Health; Developmental Biology and Cancer Section ; London, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Flutter
authors.affiliation: University College London Institute of Child Health; Developmental Biology and Cancer Section ; London, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Wesemann
authors.affiliation: University College London Institute of Child Health; Developmental Biology and Cancer Section ; London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Frosch
authors.affiliation: Department of Pediatric Hematology and Oncology; University Children´s Hospital Muenster ; Muenster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
authors.affiliation: University College London Institute of Child Health; Infection, Immunity, Inflammation and Physiological Medicine Section ; London, UK.
authors.forename: Kenth
authors.initials: K
authors.lastname: Gustafsson
authors.affiliation: University College London Institute of Child Health; Developmental Biology and Cancer Section ; London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Anderson
keywords: Ewing's Sarcoma; Gamma-delta T cells; antibody-dependent cytotoxicity; neuroblastoma; translational