Combination Immunotherapy with Clinical-Scale Enriched Human γδ T cells, hu14.18 Antibody, and the Immunocytokine Fc-IL7 in Disseminated Neuroblastoma

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Abstract
Purpose: To evaluate a combined cellular and humoral immunotherapy regimen in a mouse model of disseminated human neuroblastoma. We tested combinations of clinical-grade, isolated human γδ T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7. Experimental Design: γδ T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor–mobilized donors. γδ T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on γδ T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdcscid/J mice received 1 × 106 NB-1691 neuroblastoma cells via the tail vein 5 to 6 days before therapy began. Treatment, for five consecutive weeks, consisted of injections of 1 × 106 γδ T cells weekly, 1 × 106 γδ T cells weekly, and 20 μg hu14.18 antibody four times per week, or 1 × 106 γδ T cells weekly with 20 μg hu14.18 antibody four times per week, and 20 μg Fc-IL7 once weekly. Results: The natural cytotoxicity of γδ T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured γδ T cells viable. Combination therapy with γδ T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with γδ T cells, hu14.18 antibody, and Fc-IL7 (P = 0.005). Inclusion of Fc-IL7 offered an additional survival benefit (P = 0.04). Conclusions: We have shown a new and promising immunotherapy regimen for neuroblastoma that requires clinical evaluation. Our approach might also serve as a therapeutic model for other malignancies.