Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma.
BACKGROUND
Although a whole tumor cell vaccine strategy based on the synergistic action of granulocyte macrophage-colony-stimulating factor (GM-CSF) transduced tumor cells and CpG oligodeoxynucleotides induces potent tumor-specific immunity, such therapy is not curative in the face of large established tumors.


OBJECTIVE
The primary goal of this study was to determine if combining surgical resection of the tumor with whole tumor cell vaccination is an effective therapeutic strategy for established neuroblastoma. We also wished to determine if the phenotype of the immune response generated by this vaccine strategy was altered by the presence of bulky established tumor.


METHODS
The murine neuroblastoma model was used in which syngeneic Neuro-2a was grown subcutaneously in A/J mouse. The whole tumor cell vaccine consisted of irradiated Neuro-2a as the vehicle for tumor antigens admixed with GM-CSF and CpG oligonucleotides (100 microg).


RESULTS
In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-gamma from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-gamma production from vaccinated splenocytes was reversed after resection of the primary tumor. The use of prepared GM-CSF-secreting bystander cells simplified production of an autologous whole tumor cell vaccine that was remarkably effective in curing large tumors when combined with tumor excision.


CONCLUSIONS
These findings suggest that at least part of the immunosuppressive effects of the cancer can be reversed after surgical excision of the primary tumor. Thus, in the context of minimal residual disease, this dendritic cell-targeted immunotherapeutic approach may prove effective for the treatment of neuroblastoma.
Ohashi
Kensuke
K
Department of Surgery, Roy J. and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Kobayashi
Gen
G
Fang
Sandy
S
Zhu
Xiaoyan
X
Antonia
Scott J
SJ
Krieg
Arthur M
AM
Sandler
Anthony D
AD
D000818:Animals; D024201:Bystander Effect; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology* / Q000601:surgery / Q000628:therapy*; D009838:Oligodeoxyribonucleotides; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D014182:Transplantation, Autologous
D019496:Cancer Vaccines; C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA