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PMID: 24535937 Published · ppublish English Clinical Trial, Phase I Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer immunology research ·Vol. 2 ·No. 1 ·2014-01-00 ·Pages 37-49

Odunsi K, Matsuzaki J, James SR, Mhawech-Fauceglia P, Tsuji T, Miller A, Zhang W, Akers SN, Griffiths EA, Miliotto A, Beck A, Batt CA, Ritter G, Lele S, Gnjatic S, Karpf AR

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.

MeSH Terms
Adult Aged Antigens, Neoplasm/genetics,immunology Antineoplastic Combined Chemotherapy Protocols/pharmacology,therapeutic use Azacitidine/administration & dosage,analogs & derivatives Cancer Vaccines/genetics,immunology Carcinoma, Ovarian Epithelial Cell Line, Tumor DNA Methylation Decitabine Doxorubicin/administration & dosage,analogs & derivatives Epigenesis, Genetic/drug effects Female Gene Expression Humans Immunity, Humoral Immunotherapy, Active Long Interspersed Nucleotide Elements Membrane Proteins/genetics,immunology Middle Aged Neoplasm Recurrence, Local Neoplasms, Glandular and Epithelial/genetics,immunology,therapy Ovarian Neoplasms/genetics,immunology,pathology,therapy Polyethylene Glycols/administration & dosage T-Lymphocyte Subsets/immunology Treatment Outcome
Chemicals
Antigens, Neoplasm CTAG1B protein, human Cancer Vaccines Membrane Proteins liposomal doxorubicin Polyethylene Glycols Decitabine Doxorubicin Azacitidine
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Odunsi Kunle
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.
Matsuzaki Junko
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
James Smitha R
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Mhawech-Fauceglia Paulette
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Tsuji Takemasa
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Miller Austin
Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Zhang Wa
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198.
Akers Stacey N
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Griffiths Elizabeth A
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Miliotto Anthony
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Beck Amy
Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Batt Carl A
Department of Food Science, Cornell University, Ithaca, NY, 14853.
Ritter Gerd
Ludwig Institute for Cancer Research, NY Branch at Memorial Sloan Kettering, New York, NY, 10021.
Lele Shashikant
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Gnjatic Sacha
Tisch Cancer Institute, Mount Sinai School of Medicine, Omaha, NE, 68198.
Karpf Adam R
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198.
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Article Info
Journal
Cancer immunology research
Abbr.
Cancer Immunol Res
ISSN
2326-6074
DOI
10.1158/2326-6066.CIR-13-0126
Published
2014-01-00
Pages
37-49
Language
English
Region
United States
NLM ID
101614637
PMCID
PMC3925074
Subset
IM
Grants
NCI NIH HHS · R01 CA116674 · United States
NCI NIH HHS · P30 CA016056 · United States
NCI NIH HHS · T32 CA108456 · United States
NCI NIH HHS · CA158318 · United States
NCI NIH HHS · NIH RO1CA116674 · United States
NCI NIH HHS · R01 CA158318 · United States
External Links
PubMed source DOI: 10.1158/2326-6066.CIR-13-0126 PMC Full Text View journal details
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