Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma

Kensuke Ohashi, Gen Kobayashi, Sandy H Fang, Xiaoyan Zhu, Scott J. Antonia, Arthur M. Krieg, Anthony D. Sandler

Research output: Contribution to journalArticle

Abstract

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. Purpose: 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 μg). Results: In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-γ from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-γ 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.

Original languageEnglish (US)
Pages (from-to)1361-1368
Number of pages8
JournalJournal of Pediatric Surgery
Volume41
Issue number8
DOIs
StatePublished - Aug 2006
Externally publishedYes

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Neuroblastoma
Vaccination
Neoplasms
Cancer Vaccines
Therapeutics
Granulocyte-Macrophage Colony-Stimulating Factor
Dendritic Cells
Vaccines
Oligodeoxyribonucleotides
Residual Neoplasm
Neoplasm Antigens
Immunosuppressive Agents
Oligonucleotides
Interferons
Immunity
Phenotype
Antigens

Keywords

  • CpG
  • GM-CSF
  • Immunostimulatory DNA
  • Immunotherapy
  • Minimal residual disease
  • Neuroblastoma
  • Oligodeoxynucleotide
  • Tumor vaccine

ASJC Scopus subject areas

  • Surgery

Cite this

Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma. / Ohashi, Kensuke; Kobayashi, Gen; Fang, Sandy H; Zhu, Xiaoyan; Antonia, Scott J.; Krieg, Arthur M.; Sandler, Anthony D.

In: Journal of Pediatric Surgery, Vol. 41, No. 8, 08.2006, p. 1361-1368.

Research output: Contribution to journalArticle

Ohashi, Kensuke ; Kobayashi, Gen ; Fang, Sandy H ; Zhu, Xiaoyan ; Antonia, Scott J. ; Krieg, Arthur M. ; Sandler, Anthony D. / Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma. In: Journal of Pediatric Surgery. 2006 ; Vol. 41, No. 8. pp. 1361-1368.
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abstract = "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. Purpose: 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 μg). Results: In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-γ from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-γ 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.",
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T1 - Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma

AU - Ohashi, Kensuke

AU - Kobayashi, Gen

AU - Fang, Sandy H

AU - Zhu, Xiaoyan

AU - Antonia, Scott J.

AU - Krieg, Arthur M.

AU - Sandler, Anthony D.

PY - 2006/8

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N2 - 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. Purpose: 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 μg). Results: In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-γ from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-γ 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.

AB - 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. Purpose: 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 μg). Results: In the presence of large tumors, dendritic cells were effectively activated by the vaccine, but secretion of intereferon-γ from vaccinated splenocytes in response to antigen stimulation was suppressed. The tumor's inhibitory effect on interferon-γ 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.

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