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

Authors' Affiliations: Departments of ¹ Hematology-Oncology and ² Animal Resources Center, St. Jude Children's Research Hospital, Memphis, Tennessee, and ³ EMD Lexigen Research Center, Billerica, Massachusetts

Requests for reprints: Mario Otto, Department of Hematology-Oncology, St. Jude Children's Research Hospital, Mailstop 321, 332 North Lauderdale Street, Memphis, TN 38105-2794. Phone: 901-495-3695; Fax: 901-495-4023; E-mail: mario.otto{at}stjude.org.

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 T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7.

Experimental Design: T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor–mobilized donors. T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdc^scid/J mice received 1 x 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 x 10⁶ T cells weekly, 1 x 10⁶ T cells weekly, and 20 µg hu14.18 antibody four times per week, or 1 x 10⁶ 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 T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured T cells viable. Combination therapy with T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with 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.