Ovarian Cancer

Ovarian cancer is one of the major cancer types for which powerful, immune-based cancer treatments are now in development. This page features information on ovarian cancer and immunotherapy clinical trials for ovarian cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to ovarian cancer patients.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States. Although it is the 9th most commonly diagnosed cancer in women, it is the 5th most deadly. Ovarian cancer is sometimes called “the cancer that whispers,” because the disease often progresses before symptoms arise.

Despite advances in surgery and chemotherapy over the past 20 years, only modest progress has been made in improving overall survival in patients with ovarian cancer. Although the majority of women with advanced ovarian cancer respond to first-line chemotherapy, most responses are not durable. More than 70% of patients die of recurrent disease within 5 years of diagnosis.

The poor survival in advanced ovarian cancer is due both to late diagnosis, as well as to the lack of effective second-line therapy for patients who relapse. The clinical course of ovarian cancer patients is marked by periods of remission and relapse of sequentially shortening duration until chemotherapy resistance develops. Therefore, new treatment modalities and paradigms are needed in order to significantly improve the prognosis of women diagnosed with epithelial ovarian cancer.

Brief Statistics

Urgent Need: Ovarian cancer is the leading cause of death from gynecologic cancer in the United States. If diagnosed at the localized stage, the 5-year survival rate is 93%, however, only 15% of all cases are detected at this stage. The majority of cases (63%) are diagnosed after the disease has already spread, called metastasis. For women diagnosed with distant metastases, the 5-year survival rate is 27%.

Incidence and Mortality: Each year nearly 22,280 women in the United States will be diagnosed with ovarian cancer, and 15,500 will die. Worldwide, nearly 225,000 women will be diagnosed, and more than 140,000 will die of the disease. The incidence of ovarian cancer increases with age and is most prevalent in the eighth decade of life. The median age at the time of diagnosis is 63 years.

Signs and Symptoms: Early ovarian cancer usually has no obvious symptoms. Some women may experience persistent, nonspecific symptoms, such as bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, or urinary urgency or frequency. The most common sign is enlargement of the abdomen, which is caused by the accumulation of fluid.

Risk Factors: The most important risk factor is a strong family history of breast or ovarian cancer. Women who have had breast cancer or who have tested positive for inherited mutations in BRCA1 or BRCA2 genes are at increased risk. Studies indicate that preventive surgery to remove the ovaries and fallopian tubes in these women can decrease the risk of ovarian cancer. Other factors associated with increased risk include pelvic inflammatory disease, Lynch syndrome, postmenopausal estrogen therapy, tobacco smoking, and body weight. Pregnancy, long-term use of oral contraceptives, and tubal ligation reduce the risk of developing ovarian cancer; hysterectomy also appears to decrease risk.

Early Detection: Because of the obscure location of the ovary, ovarian cancer is usually diagnosed after regional or distant metastasis. There is currently no sufficiently accurate screening test proven to be effective in the early detection of ovarian cancer. Screening methods to detect early stage ovarian cancer are being evaluated in large-scale clinical trials, however, to date none has been shown to affect ovarian cancer mortality.

Treatment: First-line treatment for ovarian cancer includes surgery followed by a chemotherapy regimen combining a platinum-based (usually carboplatin) and a taxane-based (usually paclitaxel) treatment, which achieves complete remission in approximately 80% of patients. Patients who respond but who relapse after a period of six months or more may undergo the same therapy. Patients who progress during first-line treatment or who relapse within six months following successful first-line treatment are considered refractory or resistant to platinum-based treatments. For these patients, there are several chemotherapeutic options, however, each has shown only marginal benefit. Therefore, patients with platinum-resistant disease are encouraged to enter clinical trials.

When Should Ovarian Cancer Patients Consider A Clinical Trial?

Except for women with stage I, grade I tumors (in whom survival is greater than 95% after comprehensive surgery), patients in all other stages of ovarian cancer are encouraged to enter clinical trials for both primary and recurrence therapy. Specifically, clinical trials may be recommended for the following:

• Patients with stage II, III, and IV ovarian cancer who are in complete remission after first-line treatment
• If cancer doesn’t respond to or progresses during first-line treatment
• Cancer recurs within 6 months of first-line treatment after complete remission
• Cancer that is stage II, III, or IV and only partly responds to chemotherapy (“partly shrunk”)
• Cancer recurs more than 6 months after complete remission with first-line chemotherapy
• Cancer responds to second or subsequent lines of chemotherapy, but recurs again

Go to our Cancer Immunotherapy Clinical Trial Finder to find clinical trials of immunotherapies for ovarian cancer that are currently enrolling patients.

Why Consider Immunotherapy Clinical Trials for Ovarian Cancer?

Clinical relapse is the major cause of death from ovarian cancer, and there is a great unmet need for new therapies that can prevent cancer recurrence and extend survival. Immunotherapies that can eradicate residual disease and establish a sustained immune system response against recurring cancer cells may help overcome this major challenge in ovarian cancer, leading to long-term “cures” for more ovarian cancer patients.

Scientific Foundations for Ovarian Cancer Immunotherapy

Immunotherapy as a potentially promising approach for treatment of ovarian cancer is based on several lines of evidence. The earliest and one of the most striking came from observations that the presence of infiltrating T cells (called “tumor-infiltrating lymphocytes,” or TILs) in ovarian tumors is positively and strongly associated with improved survival of patients with ovarian cancer. A study in 2003 of 186 samples from patients with stage III or IV ovarian cancers showed that patients whose tumors contained infiltrating T cells had significantly improved 5-year overall survival [1]. A later study by CRI scientists showed that patients with higher frequencies of infiltrating killer T cells had improved survival [2]. Together, these and other findings strongly suggest that immunotherapies that can induce or enhance optimal immunologic conditions within ovarian cancers may hold great promise for extending the lives of ovarian cancer patients.

Also, scientists have identified several ovarian cancer-related antigens—molecules on or in cells that are capable of eliciting an immune response—that can serve as targets for immune recognition and attack. These include several “cancer-testis” antigens, which can induce powerful anti-cancer immune responses and which are expressed only by cancer and not by healthy tissues (with the exception of the testis and, occasionally, placenta), making them highly promising targets for cancer immunotherapy. One of these, NY-ESO-1, is under intense investigation by researchers in our global cancer immunotherapy clinical trials network, the Cancer Vaccine Collaborative (CVC), a partnership between CRI and the Ludwig Institute for Cancer Research. Research by CVC investigator Kunle Odunsi, M.D., Ph.D., has shown that aberrant NY-ESO-1 expression may be found in up to 43% of ovarian cancers.

Other antigens that are expressed in ovarian cancer include: CA-125 (also a peripheral marker of ovarian cancer presence and relapse), HER2/neu, MUC1, MAGE, OA3, membrane folate receptor, TAG-72, mesothelin, sialyl-Tn, p53, survivin, and TERT. Strategies to target these antigens currently include antibodies targeting CA-125, which is elevated in 79% of all patients with ovarian cancer, as well as antigen-specific vaccines targeting HER2, NY-ESO-1, p53 (Leiden), folate binding protein (E39 peptide), and dendritic cell vaccines targeting defined tumor antigens, such as TERT/survivin, or patient- or tumor-specific antigens, including treatments such as CVac.

See our Cancer Immunotherapy Pipeline for more information about ovarian cancer immunotherapies in late-stage development.

(Slide above shows expression of NY-ESO-1 in ovarian cancer. Image provided by K. Odunsi.)

Promising Advances and CRI Impact

Since 1985, CRI has made more than 70 grants totaling nearly $10 million in new research and treatment approaches for ovarian cancer. Through the CVC, CRI has supported 6 clinical trials in ovarian cancer that have enrolled more than 100 patients. Through these trials and related laboratory studies, CRI investigators have made several important discoveries that have led to promising advances in the treatment of ovarian cancer. More recent studies have also demonstrated that these treatments can lengthen the time before an ovarian cancer patient relapses.

In one study by CRI Anna-Maria Kellen Clinical Investigator Kunle Odunsi, M.D., Ph.D., at Roswell Park Cancer Institute, patients in first remission treated with a NY-ESO-1 cancer vaccine utilizing a prime-boost strategy showed a median time to progression of 21 months compared with a historical average of 16 months among this patient population, suggesting that the vaccine might help extend the lives of patients with ovarian cancer in first remission [3]. The most recent CVC trial in ovarian cancer patients suggests even more promising results. In a clinical trial at Weill Cornell Medical College, CVC scientists treated 28 patients with ovarian cancer in second or third remission using a cancer vaccine composed of overlapping peptides of NY-ESO-1 administered with the immune stimulants Montanide® and Poly-ICLC (Hiltonol®). The combination was successful in achieving the most powerful anti-cancer immune responses seen to date in a CVC trial. Moreover, patients whose cancers expressed the NY-ESO-1 vaccine target had an average time to progression of 22 months, compared to an average of 4 months among patients whose cancers lacked NY-ESO-1 expression [4]. The time to relapse of 22 months is particularly notable because this interval for patients in second or third remission is typically shorter than for patients in first remission, with averages from 4 to 10 months or less. The results of the study provide an important foundation for further clinical development of this immunotherapeutic strategy, particularly in combination with anti-CTLA-4 and other checkpoint blockade therapies.

CRI-funded studies in the CVC have also shown that targeting multiple immunosuppressive pathways in ovarian cancer may be another promising approach. CD8+ killer T cells homing to cancer cells that express NY-ESO-1 often become less effective at attacking cancer cells upon entering the ovarian tumor microenvironment. Dr. Odunsi and other CVC researchers have shown that two inhibitory molecules, PD-1 and LAG-3, collaborate in suppressing the anti-tumor T cell immune response [5]. Moreover, by giving a combination of antibodies that block PD-1 and LAG-3, they could restore T cells to full function resulting in stronger anti-tumor immunity. Dr. Odunsi and members of CRI’s Ovarian Cancer Working Group have also shown that the enzyme indoleamine-2,3-dioxygenase (IDO) is critical in mediating immunosuppression in the ovarian tumor microenvironment, and that blocking IDO can successfully prevent tumor-mediated suppression of T cells.

Other CRI researchers and projects that are opening up new avenues in cancer immunotherapy include:

• Members of the Ovarian Cancer Working Group and Cancer Vaccine Collaborative Danila Valmori, Ph.D., and Maha Ayyoub, Ph.D., at the Centre de Lutte Contre le Cancer-Nantes Atlantique in France, have made important discoveries about the roles and characteristics of different immune cells in ovarian cancer, including the Th17 subset of helper T cells and regulatory T cells. Their studies are giving us important clues about how we can effectively target different immune cell subsets to improve ovarian cancer immunotherapy.

• Juan R. Cubillos-Ruiz, Ph.D., a 2012-2014 CRI Postdoctoral Fellow at Weill Cornell Medical College, is working to understand how dendritic cells (DCs), immune cells responsible for activating and “training” other immune cells, acquire pro-tumor properties in the ovarian cancer. His goal is to develop strategies to re-educate DCs to promote anti-cancer immune responses. He has found a protein, XBP1, that may represent a highly promising target for immunotherapies aimed at boosting pre-existing anti-ovarian cancer immune responses. He is also exploring how therapies that target XBP1 might synergize with other immunotherapies such as adoptive T cell transfer and CD40 antibodies.

• Paola Betancur, Ph.D., a 2012-2015 CRI Postdoctoral Fellow, and Diane Tseng, 2012-2014 STaRT Graduate Student, both at Stanford University School of Medicine, are working to validate and test therapeutic strategies targeting the CD47 protein to treat cancer. CD47 provides a “don’t eat me” signal to macrophages, a type of white blood cell that engulfs and digests dead and harmful cells. This may be a key way that cancer avoids immune attack. Studies have shown that treatment with an anti-CD47 antibody can shrink tumors drastically in models of numerous cancers, including ovarian cancer. Paola Betancur and Diane Tseng are working to understand the fundamental biologic mechanisms of anti-CD47 therapy and how to improve it for patients.

Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2012, GLOBOCAN 2008, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov, CRI grantee progress reports and other documents, Jemal, Siegel et al. 2009, Jemal, Siegel et al. 2010