title: Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer.
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.
authors.affiliation: 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.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Smitha R
authors.initials: SR
authors.lastname: James
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198.
authors.forename: Wa
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Akers
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Griffiths
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Anthony
authors.initials: A
authors.lastname: Miliotto
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Amy
authors.initials: A
authors.lastname: Beck
authors.affiliation: Department of Food Science, Cornell University, Ithaca, NY, 14853.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Batt
authors.affiliation: Ludwig Institute for Cancer Research, NY Branch at Memorial Sloan Kettering, New York, NY, 10021.
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Lele
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, Omaha, NE, 68198.
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006801:Humans; D056724:Immunity, Humoral; D016233:Immunotherapy, Active; D020084:Long Interspersed Nucleotide Elements; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000276:immunology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D008565:Membrane Proteins; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000077209:Decitabine; D004317:Doxorubicin; D001374:Azacitidine