Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines.

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 adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating 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 successfully manufactured 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 14 Pg. 3178-86 (Jul 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25805798 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cancer Vaccines
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Adolescent
• Adult
• Cancer Vaccines (immunology, therapeutic use)
• Child
• Enzyme-Linked Immunosorbent Assay
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology, metabolism)
• Humans
• Male
• Middle Aged
• Sarcoma, Alveolar Soft Part (therapy)
• Sarcoma, Clear Cell (therapy)
• Soft Tissue Neoplasms (therapy)
• Young Adult