Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer

Jonathan W. Simons, Elizabeth Jaffee, Christine E. Weber, Hyam I. Levitsky, William G Nelson, Michael A Carducci, Audrey J. Lazenby, Lawrence K. Cohen, Christy C. Finn, Shirley M. Clift, Karen M. Hauda, Lisa A. Beck, Kristen M. Leiferman, Albert H. Owens, Steven Piantadosi, Glenn Dranoff, Richard C. Mulligan, Andrew Mark Pardoll, Fray F. Marshall

Research output: Contribution to journalArticle

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene- transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose- escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication- defective retroviral vector MFG was used for GM-CSF gene transfer. No dose- limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

Original languageEnglish (US)
Pages (from-to)1537-1546
Number of pages10
JournalCancer Research
Volume57
Issue number8
StatePublished - 1997

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Granulocyte-Macrophage Colony-Stimulating Factor
Renal Cell Carcinoma
Vaccines
Cancer Vaccines
Genes
Delayed Hypersensitivity
Eosinophils
T-Lymphocytes
Safety
Intradermal Injections
Feasibility Studies
Retroviridae
Dendritic Cells
Autoimmune Diseases
Neutrophils
Macrophages
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. / Simons, Jonathan W.; Jaffee, Elizabeth; Weber, Christine E.; Levitsky, Hyam I.; Nelson, William G; Carducci, Michael A; Lazenby, Audrey J.; Cohen, Lawrence K.; Finn, Christy C.; Clift, Shirley M.; Hauda, Karen M.; Beck, Lisa A.; Leiferman, Kristen M.; Owens, Albert H.; Piantadosi, Steven; Dranoff, Glenn; Mulligan, Richard C.; Pardoll, Andrew Mark; Marshall, Fray F.

In: Cancer Research, Vol. 57, No. 8, 1997, p. 1537-1546.

Research output: Contribution to journalArticle

Simons, JW, Jaffee, E, Weber, CE, Levitsky, HI, Nelson, WG, Carducci, MA, Lazenby, AJ, Cohen, LK, Finn, CC, Clift, SM, Hauda, KM, Beck, LA, Leiferman, KM, Owens, AH, Piantadosi, S, Dranoff, G, Mulligan, RC, Pardoll, AM & Marshall, FF 1997, 'Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer', Cancer Research, vol. 57, no. 8, pp. 1537-1546.
Simons, Jonathan W. ; Jaffee, Elizabeth ; Weber, Christine E. ; Levitsky, Hyam I. ; Nelson, William G ; Carducci, Michael A ; Lazenby, Audrey J. ; Cohen, Lawrence K. ; Finn, Christy C. ; Clift, Shirley M. ; Hauda, Karen M. ; Beck, Lisa A. ; Leiferman, Kristen M. ; Owens, Albert H. ; Piantadosi, Steven ; Dranoff, Glenn ; Mulligan, Richard C. ; Pardoll, Andrew Mark ; Marshall, Fray F. / Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. In: Cancer Research. 1997 ; Vol. 57, No. 8. pp. 1537-1546.
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abstract = "Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene- transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose- escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication- defective retroviral vector MFG was used for GM-CSF gene transfer. No dose- limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.",
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T1 - Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer

AU - Simons, Jonathan W.

AU - Jaffee, Elizabeth

AU - Weber, Christine E.

AU - Levitsky, Hyam I.

AU - Nelson, William G

AU - Carducci, Michael A

AU - Lazenby, Audrey J.

AU - Cohen, Lawrence K.

AU - Finn, Christy C.

AU - Clift, Shirley M.

AU - Hauda, Karen M.

AU - Beck, Lisa A.

AU - Leiferman, Kristen M.

AU - Owens, Albert H.

AU - Piantadosi, Steven

AU - Dranoff, Glenn

AU - Mulligan, Richard C.

AU - Pardoll, Andrew Mark

AU - Marshall, Fray F.

PY - 1997

Y1 - 1997

N2 - Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene- transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose- escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication- defective retroviral vector MFG was used for GM-CSF gene transfer. No dose- limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene- transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose- escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication- defective retroviral vector MFG was used for GM-CSF gene transfer. No dose- limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

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