Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines

John M. Goldberg, David E. Fisher, George D. Demetri, Donna Neuberg, Stephen A. Allsop, Catia Fonseca, Yukoh Nakazaki, David Nemer, Chandrajit P. Raut, Suzanne George, Jeffrey A. Morgan, Andrew J. Wagner, Gordon J. Freeman, Jerome Ritz, Cecilia Lezcano, Martin Mihm, Christine Canning, F. Stephen Hodi, Glenn Dranoff

Research output: Contribution to journalArticle

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Abstract

Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviralmediated gene transfer to secrete granulocyte-macrophage colonystimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfullymanufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8+ T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.

Original languageEnglish (US)
Pages (from-to)3178-3186
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

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Alveolar Soft Part Sarcoma
Clear Cell Sarcoma
Granulocyte-Macrophage Colony-Stimulating Factor
Vaccines
Granulocytes
Sarcoma
Neoplasms
Vaccination
Macrophages
Immunization
Microphthalmia-Associated Transcription Factor
Angiopoietin-2
Angiopoietin-1
T-Lymphocytes
Genetic Translocation
Clinical Trials, Phase I
Delayed Hypersensitivity
Tissue Plasminogen Activator
Dendritic Cells
Antibody Formation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines. / Goldberg, John M.; Fisher, David E.; Demetri, George D.; Neuberg, Donna; Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; Raut, Chandrajit P.; George, Suzanne; Morgan, Jeffrey A.; Wagner, Andrew J.; Freeman, Gordon J.; Ritz, Jerome; Lezcano, Cecilia; Mihm, Martin; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn.

In: Clinical Cancer Research, Vol. 21, No. 14, 15.07.2015, p. 3178-3186.

Research output: Contribution to journalArticle

Goldberg, JM, Fisher, DE, Demetri, GD, Neuberg, D, Allsop, SA, Fonseca, C, Nakazaki, Y, Nemer, D, Raut, CP, George, S, Morgan, JA, Wagner, AJ, Freeman, GJ, Ritz, J, Lezcano, C, Mihm, M, Canning, C, Hodi, FS & Dranoff, G 2015, 'Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines', Clinical Cancer Research, vol. 21, no. 14, pp. 3178-3186. https://doi.org/10.1158/1078-0432.CCR-14-2932
Goldberg, John M. ; Fisher, David E. ; Demetri, George D. ; Neuberg, Donna ; Allsop, Stephen A. ; Fonseca, Catia ; Nakazaki, Yukoh ; Nemer, David ; Raut, Chandrajit P. ; George, Suzanne ; Morgan, Jeffrey A. ; Wagner, Andrew J. ; Freeman, Gordon J. ; Ritz, Jerome ; Lezcano, Cecilia ; Mihm, Martin ; Canning, Christine ; Hodi, F. Stephen ; Dranoff, Glenn. / Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 14. pp. 3178-3186.
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abstract = "Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviralmediated gene transfer to secrete granulocyte-macrophage colonystimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfullymanufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8+ T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.",
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T1 - Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines

AU - Goldberg, John M.

AU - Fisher, David E.

AU - Demetri, George D.

AU - Neuberg, Donna

AU - Allsop, Stephen A.

AU - Fonseca, Catia

AU - Nakazaki, Yukoh

AU - Nemer, David

AU - Raut, Chandrajit P.

AU - George, Suzanne

AU - Morgan, Jeffrey A.

AU - Wagner, Andrew J.

AU - Freeman, Gordon J.

AU - Ritz, Jerome

AU - Lezcano, Cecilia

AU - Mihm, Martin

AU - Canning, Christine

AU - Hodi, F. Stephen

AU - Dranoff, Glenn

PY - 2015/7/15

Y1 - 2015/7/15

N2 - Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviralmediated gene transfer to secrete granulocyte-macrophage colonystimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfullymanufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8+ T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.

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