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

Kunle Odunsi, Junko Matsuzaki, Smitha R. James, Paulette Mhawech-Fauceglia, Takemasa Tsuji, Austin Miller, Wa Zhang, Stacey N. Akers, Elizabeth A. Griffiths, Anthony Miliotto, Amy Beck, Carl A. Batt, Gerd Ritter, Shashikant Lele, Sacha Gnjatic, Adam R Karpf

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-49
Number of pages13
JournalCancer immunology research
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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