Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (T H 1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-g secretions in autologous T cells. These DCs produced the highest levels of T H 1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCloxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers.

Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1 cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1 cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1 tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.

Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute–designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease ( Ptrend < .001), and from 41% to 62% in stage IV disease ( Ptrend < .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P < .001) and from 27% to 61% ( P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have ≥ 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P ≤ .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or ≤ 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients.

Purpose Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate endometriosis and ovarian cancer patients from healthy individuals. Experimental design We conducted a two-stage exploratory study to investigate the utility of plasma miRNA profiling to differentiate between endometriosis, endometriosis-associated ovarian cancer (EAOC) and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n=6), endometriosis (n=7), and EAOC (n=7) patients based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n=88) of healthy individuals (n =20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC, n= 21, included as controls). Results We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, endometriosis, and EAOC patients. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease-specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOC were mirrored in a double transgenic mouse EAOC model. Conclusion Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases.

Although the use of IP/IV chemotherapy increased significantly at National Comprehensive Cancer Network centers between 2003 and 2012, fewer than 50% of eligible patients received it. Increasing IP/IV chemotherapy use in clinical practice may be an important and underused strategy to improve ovarian cancer outcomes.

Purpose Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). Experimental design RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n=32), benign endometriosis (n=30), atypical endometriosis (n=15) and EAOC (n=43). Serous tumors (n=15) were included as non-endometriosis associated controls. The immune microenvironment was profiled using Nanostring and the nCounter® GX Human Immunology Kit, comprising probes for a total of 511 immune genes. Results One third of the endometriosis patients revealed a tumor-like inflammation profile, suggesting that cancer–like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial (OSE) cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. Conclusions These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC.

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