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Clin Cancer Res. 2015 Jul 15;21(14):3178-86. doi: 10.1158/1078-0432.CCR-14-2932. Epub 2015 Mar 24.

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

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
3
Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Cancer Vaccine Center, Center for Immuno-oncology, and Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Surgical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
8
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts.
9
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
10
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
11
Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Cancer Vaccine Center, Center for Immuno-oncology, and Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
12
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Cancer Vaccine Center, Center for Immuno-oncology, and Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, Massachusetts. glenn_dranoff@dfci.harvard.edu.

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.

PMID:
25805798
PMCID:
PMC4506240
DOI:
10.1158/1078-0432.CCR-14-2932
[Indexed for MEDLINE]
Free PMC Article

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