Combination immunotherapy with clinical-scale enriched human gammadelta T cells, hu14.18 antibody, and the immunocytokine Fc-IL7 in disseminated neuroblastoma.
OBJECTIVE
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 gammadelta T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7.


METHODS
gammadelta T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor-mobilized donors. gammadelta T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on gammadelta T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdc(scid)/J mice received 1 x 10(6) 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 10(6) gammadelta T cells weekly, 1 x 10(6) gammadelta T cells weekly, and 20 microg hu14.18 antibody four times per week, or 1 x 10(6) gammadelta T cells weekly with 20 microg hu14.18 antibody four times per week, and 20 mug Fc-IL7 once weekly.


RESULTS
The natural cytotoxicity of gammadelta T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured gammadelta T cells viable. Combination therapy with gammadelta T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with gammadelta 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.
Otto
Mario
M
Department of Hematology-Oncology and Animal Resources Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Barfield
Raymond C
RC
Martin
William J
WJ
Iyengar
Rekha
R
Leung
Wing
W
Leimig
Thasia
T
Chaleff
Stanley
S
Gillies
Stephen D
SD
Handgretinger
Rupert
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001782:Blood Donors; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005732:Gangliosides / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D015851:Interleukin-7 / Q000276:immunology; D007937:Leukapheresis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D015851:Interleukin-7; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016179:Granulocyte Colony-Stimulating Factor; C019403:ganglioside, GD2