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Cancer Immunol Res. 2014 Jan;2(1):37-49. doi: 10.1158/2326-6066.CIR-13-0126.

Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer.

Author information

1
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
2
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
3
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
4
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
5
Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
6
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198.
7
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
8
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263.
9
Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
10
Department of Food Science, Cornell University, Ithaca, NY, 14853.
11
Ludwig Institute for Cancer Research, NY Branch at Memorial Sloan Kettering, New York, NY, 10021.
12
Tisch Cancer Institute, Mount Sinai School of Medicine, Omaha, NE, 68198.

Abstract

The cancer-testis/cancer-germline antigen NY-ESO-1 is a vaccine target in epithelial ovarian cancer (EOC), but its limited expression is a barrier to vaccine efficacy. As NY-ESO-1 is regulated by DNA methylation, we hypothesized that DNA methyltransferase (DNMT) inhibitors may augment NY-ESO-1 vaccine therapy. In agreement, global DNA hypomethylation in EOC was associated with the presence of circulating antibodies to NY-ESO-1. Pre-clinical studies using EOC cell lines showed that decitabine treatment enhanced both NY-ESO-1 expression and NY-ESO-1-specific CTL-mediated responses. Based on these observations, we performed a phase I dose-escalation trial of decitabine, as an addition to NY-ESO-1 vaccine and doxorubicin liposome (doxorubicin) chemotherapy, in 12 patients with relapsed EOC. The regimen was safe, with limited and clinically manageable toxicities. Both global and promoter-specific DNA hypomethylation occurred in blood and circulating DNAs, the latter of which may reflect tumor cell responses. Increased NY-ESO-1 serum antibodies and T cell responses were observed in the majority of patients, and antibody spreading to additional tumor antigens was also observed. Finally, disease stabilization or partial clinical response occurred in 6/10 evaluable patients. Based on these encouraging results, evaluation of similar combinatorial chemo-immunotherapy regimens in EOC and other tumor types is warranted.

PMID:
24535937
PMCID:
PMC3925074
DOI:
10.1158/2326-6066.CIR-13-0126
[Indexed for MEDLINE]
Free PMC Article

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