Cancer Immunotherapy

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 80% of patients will have a recurrence of their disease after first-line treatment, and more than half will 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 92%, however, only 15% of all cases are detected at this stage. The majority of cases (61%) are diagnosed after the disease has already spread (metastasized). For women diagnosed with distant metastases, the 5-year survival rate is 27%.

Incidence and Mortality: Each year nearly 22,240 women in the United States will be diagnosed with ovarian cancer, and 14,230  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. About half of the women diagnosed with ovarian cancer are 63 years or older.

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 there are no obvious early symptoms, 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 reduce 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 a complete response in approximately 80% of patients. (A complete response means no visible evidence of disease on imaging scans and normal blood tests.) 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?

Women with stage I, grade I tumors (in whom survival is greater than 95% after comprehensive surgery), do not generally need to consider clinical trials. 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, and the patient is in remission;
  • Cancer responds to second or subsequent lines of chemotherapy, but recurs again

Several experimental treatments, including targeted therapies like bevacizumab (Avastin®) and cediranib, are being tested in late-phase clinical trials for patients with ovarian cancer. As well, a number of newer immune-based therapies are being investigated in early-phase clinical trials for patients with ovarian cancer.

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 remissions or “cures” for more ovarian cancer patients.

 

WHAT TYPES OF IMMUNOTHERAPIES ARE AVAILABLE FOR OVARIAN CANCER?

Current immunotherapies for ovarian cancer fall into three broad categories: immune checkpoint inhibitors; therapeutic vaccines; and adoptive T cell transfer. These therapies are still in early-phase testing (phase I and II) for ovarian cancer, but their successful use in other types of cancers suggests that they may ultimately prove useful for ovarian cancer as well.

Immune Checkpoint Inhibitors

A promising avenue of clinical research in ovarian cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses.

Ipilimumab (Yervoy™), which targets the CTLA-4 checkpoint molecule on activated immune cells, has been at the vanguard of this new immunotherapy approach. First tested by James P. Allison, Ph.D., the director of CRI’s Scientific Advisory Council, ipilimumab was the first treatment ever proven to extend survival in patients with metastatic melanoma, the most deadly form of skin cancer, and was approved for that indication in 2011. It is now being tested in a variety of other cancer types, including ovarian cancer, for which a phase II study (NCT01611558) is currently under way.

Two other immune checkpoint inhibitors, tremelimumab (anti-CTLA-4) and MEDI4736 (anti-PD-L1), are being tested in combination for patients with advanced solid tumors in a phase I trial sponsored jointly by the CRI/Ludwig Clinical Trials Network (NCT01975831). Patients with recurrent ovarian cancer are eligible for this clinical trial. The study is open at three institutions including Roswell Park Cancer Institute, Buffalo, NY; Memorial Sloan-Kettering Cancer Center, New York, NY; and Dana Farber Cancer Center, Boston, MA.

Therapeutic Vaccines

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 cells and not by healthy tissues (with the exception of the testis and, occasionally, placenta), making them promising targets for cancer immunotherapy. One of these, NY-ESO-1, is under intense investigation by researchers in the CRI/Ludwig Clinical Trials Network. Research by CRI investigator Kunle Odunsi, M.D., Ph.D., has shown that NY-ESO-1 expression may be found in up to 43% of ovarian cancers.

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

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.

Several phase I and II studies of antigen-based vaccines are currently recruiting patients with ovarian cancer, including:

  • A phase I trial of dendritic cell vaccine therapy given with or without sirolimus in patients with solid tumors expressing NY-ESO-1 (NCT01522820).
  • Phase I trial of sirolimus and vaccine therapy in treating patients with stage II-IV ovarian epithelial, fallopian tube, or primary peritoneal cavity cancer (NCT01536054).
  • Phase I/II trial of autologous, hapten-modified vaccine, OVAX, in patients with relapsed stage III or IV ovarian cancer (NCT00660101).
  • Phase I/II trial of vaccine therapy in recurrent platinum sensitive ovarian cancer patients. (NCT01334047).
  • Phase Ib trial of folate binding protein vaccine in ovarian cancer (NCT01580696).
  • Chemo-immunotherapy (gemcitabine, interferon-alpha 2b and p53 SLP) in patients with platinum-resistant ovarian cancer (NCT01639885).
  • Phase II trial of ovarian dendritic cell vaccine for patients with advanced ovarian cancer (NCT00703105).
  • Phase II trial of adjuvant FANG vaccine for patients with high-risk stage III/IV ovarian cancer (NCT01309230).
  • A phase II trial of salvage ovarian FANG vaccine plus bevacizumab for patients with recurrent/refractory ovarian cancer (NCT01551745).
  • A phase II trial of TroVax® versus placebo in patients with relapsed asymptomatic ovarian cancer (NCT01556841).

Adoptive T Cell Transfer

A third major avenue of immunotherapy for ovarian cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several phase I and II trials of adoptive T cell transfer techniques are currently under way for patients with ovarian cancer, including:

  • T cells genetically engineered to target CEA (carcinoembryonic antigen) are being tested in a phase II trial (NCT01723306) for patients with confirmed CEA-expressing adenocarcinomas.
  • Chemotherapy followed by transfer of allogeneic natural killer cells and IL-2 in patients with recurrent ovarian cancer (NCT01105650).
  • T cells genetically engineered to target the NY-ESO-1 tumor-specific antigen are being tested in a phase II trial (NCT00670748) for patients with metastatic cancers expressing NY-ESO-1.
  • White blood cells genetically engineered to recognize NY-ESO-1, given along with dendritic cells pulsed with NY-ESO-1 antigen as a vaccine, are being tested in a phase II trial (NCT01697527) for patients with stage IV, advanced, or refractory malignancies.
  • Phase I trial of autologous T cells combined with autologous OC-DC vaccine for patients with recurrent ovarian cancer (NCT01312376).

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


Promising Advances and CRI Impact

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.

Since 1985, CRI has made more than 70 grants totaling nearly $10 million in new research and treatment approaches for ovarian cancer. Through the Clinical Accelerator, 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]. A recent CRI-funded trial in ovarian cancer patients suggests even more promising results. In a clinical trial at Weill Cornell Medical College, CRI 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 Trials Network study. 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.

The ability of the immune system to recognize and kill cancer cells depends on T cells being able to find antigens on cancer cells. Unfortunately, not all cancer cells in a tumor are the same, and not all produce NY-ESO-1 or other cancer antigens; these cells are ones likely to escape destruction by the immune system. Researchers therefore want to find ways to prod cancer cells into making NY-ESO-1 when they otherwise would not—in effect forcing them to come out of hiding. In a 2013 paper published in the journal Cancer Immunology Research, Odunsi and colleagues describe research showing that a drug called decitabine, administered along with chemotherapy, can increase the effectiveness of a vaccine designed to elicit an immune response against the NY-ESO-1 antigen. Decitabine is a drug that stops DNA from being methylated—chemically shrouded in a way that makes it unavailable for protein synthesis. The researchers have found that NY-ESO-1 antigen DNA is commonly methylated in cancer cells. Treatment with decitabine removes this protective coating from DNA, allowing the NY-ESO-1 protein to be made. Once NY-ESO-1 is made, T cells can more easily identify, target, and kill the cancer cells producing it. Six of ten patients with refractory epithelial ovarian cancer who received this treatment showed either stable disease or had a partial regression of their tumors. Such a response in patients who had previously received multiple rounds of chemotherapy and whose tumors were considered chemo-resistant is highly encouraging, and suggests that this approach may overcome a principal mechanism by which ovarian and other cancers escape immune attack [5]. A large phase II trial testing this approach is planned for 2014.

CRI-funded studies 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 [6]. 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. Two new clinical trials that will block IDO activity will be open to ovarian cancer patients in early 2014:

  • CITN-05: A pilot study of the immunological effects of neo-adjuvant INCB024360 in patients with epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
  • RPCI Protocol I 248613: A Phase I/IIb study of DEC205mAb-NY‑ESO‑1 fusion protein (CDX‑1401) given with adjuvant poly-ICLC in combination with INCB024360 for patients in remission with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express NY‑ESO‑1 or LAGE‑1 Antigen.
  • Members of the Ovarian Cancer Working Group and CVC Trials Network 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.

SPOREs in Ovarian Cancer: SPORE stands for Specialized Program of Research Excellence. Funded by the National Cancer Institute (NCI), the program is part of a nationwide initiative designed to speed the flow of promising knowledge from the laboratory to the clinic, where it can help patients the most. The ultimate goal of this NCI initiative is to reduce cancer incidence and mortality and to improve the quality of life for cancer patients. There are currently five Ovarian Cancer SPORES and each of these includes promising immunotherapy clinical trials. Further information can be found at the SPORE website: http://trp.cancer.gov/spores/ovarian.htm.


Sources: National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2013; GLOBOCAN 2008; National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; CRI grantee progress reports and other documents


[1] Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003 Jan 16;348(3):203-13. PMID: 12529460 (http://www.ncbi.nlm.nih.gov/pubmed/12529460)

[2] Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005 Dec 20;102(51):18538-43. PMID: 16344461 (http://www.ncbi.nlm.nih.gov/pubmed/16344461)

[3] Odunsi K, Matsuzaki J, Karbach J, Neumann A, Mhawech-Fauceglia P, Miller A, Beck A, Morrison CD, Ritter G, Godoy H, Lele S, duPont N, Edwards R, Shrikant P, Old LJ, Gnjatic S, Jäger E. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc Natl Acad Sci U S A 2012 Apr 10;109(15):5797-802. PMID: 22454499 (www.ncbi.nlm.nih.gov/pubmed/22454499)

[4] Sabbatini P, Tsuji T, Ferran L, Ritter E, Sedrak C, Tuballes K, Jungbluth AA, Ritter G, Aghajanian C, Bell-McGuinn K, Hensley ML, Konner J, Tew W, Spriggs DR, Hoffman EW, Venhaus R, Pan L, Salazar AM, Diefenbach CM, Old LJ, Gnjatic S. Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clin Cancer Res 2012 Dec 1;18(23):6497-508. PMID: 23032745 (http://www.ncbi.nlm.nih.gov/pubmed/23032745)

[5] 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 A, Gnjatic S, and Karp AR. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res. 2013;2(1):1-13.

[6] Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010 Apr 27;107(17):7875-80. PMID: 20385810 (http://www.ncbi.nlm.nih.gov/pubmed/20385810)

 

Last Updated January 2014

 

Ovarian Cancer News & Stories

Reviewed By:

Kunle Odunsi is an expert in ovarian cancer immunotherapy
Kunle Odunsi, M.D., Ph.D.
Roswell Park Cancer Institute, Buffalo, NY

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