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.
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263 ; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263.
Cancer Immunol Res. 2014 Jan;2(1):37-49. doi: 10.1158/2326-6066.CIR-13-0126.
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.
癌症睾丸/癌症生殖系抗原 NY-ESO-1 是上皮性卵巢癌 (EOC) 的疫苗靶点，但它的有限表达是疫苗疗效的障碍。由于 NY-ESO-1 受 DNA 甲基化调控，我们假设 DNA 甲基转移酶 (DNMT) 抑制剂可能增强 NY-ESO-1 疫苗治疗。一致地，EOC 中存在循环针对 NY-ESO-1 的抗体与全球 DNA 低甲基化相关。使用 EOC 细胞系的临床前研究表明，地西他滨治疗增强了 NY-ESO-1 表达和 NY-ESO-1 特异性 CTL 介导的反应。基于这些观察结果，我们在 12 名复发性 EOC 患者中进行了地西他滨与 NY-ESO-1 疫苗和多柔比星脂质体 (多柔比星) 化疗联合的 I 期剂量递增试验。该方案安全，毒性有限且可临床管理。血液和循环 DNA 中均发生了全球和启动子特异性 DNA 低甲基化，后者可能反映了肿瘤细胞的反应。大多数患者观察到 NY-ESO-1 血清抗体和 T 细胞反应增加，并且还观察到抗体扩散到其他肿瘤抗原。最后，10 名可评估患者中有 6 名出现疾病稳定或部分临床反应。基于这些令人鼓舞的结果，有必要在 EOC 和其他肿瘤类型中评估类似的联合化疗免疫治疗方案。
