|
|
Combination Immunotherapy with
Clinical-Scale Enriched Human γδ T cells, hu14.18 Antibody,
and the Immunocytokine Fc-IL7 in Disseminated Neuroblastoma
Mario Otto1,
Raymond C. Barfield1,
William J. Martin2,
Rekha Iyengar1, Wing
Leung1, Thasia
Leimig1, Stanley
Chaleff1, Stephen
D. Gillies3 and Rupert
Handgretinger1
Authors' Affiliations: Departments
of 1Hematology-Oncology and 2Animal Resources
Center, St. Jude Children's Research Hospital, Memphis, Tennessee, and
3EMD 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@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 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 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 γδ T cells weekly, 1 x
106 γδ T cells weekly, and 20 µg hu14.18
antibody four times per week, or 1 x 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.
|
