Combination Of Chemotherapy And Immunotherapy May Be Effective Against Ovarian Cancer

Combination Of Chemotherapy And Immunotherapy May Be Effective Against Ovarian CancerInside each ovarian tumor, there are good cells and bad cells. A new paper explains their roles:

  • The bad cells are fibroblasts. They work to block chemotherapy, which is why nearly every woman with ovarian cancer becomes resistant to treatment.
  • The good cells are immune T cells. They can reverse that resistance.

These findings, reported in Cell, suggest a whole different way of thinking about chemotherapy resistance – and the potential to harness immunotherapy drugs to treat ovarian cancer.

“Ovarian cancer is often diagnosed at late stages, so chemotherapy is a key part of treatment. Most patients will respond to it at first, but everybody develops chemoresistance. And that’s when ovarian cancer becomes deadly,” says study author J. Rebecca Liu, M.D., associate professor of obstetrics and gynecology at the University of Michigan.

“In the past, we’ve thought the resistance was caused by genetic changes in tumor cells. But we found that’s not the whole story,” she says.

Researchers looked at tissue samples from ovarian cancer patients. They separated the cells by type to study the tumor microenvironment in cells and in mice. They also linked their findings back to actual patient outcomes.

Ovarian cancer is typically treated with cisplatin, a platinum-based chemotherapy. The researchers found that fibroblasts blocked platinum. These cells prevented platinum from accumulating in the tumor and protected tumor cells from being killed off by cisplatin.

Immune T cells, on the other hand, overruled the protection of the fibroblasts. When researchers added the immune T cells to the fibroblasts, the tumor cells began to die off.

“T cells are the soldiers of the immune system. We already know that if you have a lot of T cells in a tumor, you have better outcomes. Now we see that the immune system can also impact chemotherapy resistance,” says study author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Surgery, Immunology and Biology at the University of Michigan.

By boosting the immune T cells, the researchers were able to overcome the chemotherapy resistance in mouse models. They used interferon, a type of small protein, to manipulate the pathways involved in cisplatin.

The researchers suggest that combining chemotherapy with immunotherapy may be effective against ovarian cancer. PD-L1 and PD-1 pathway blockers are FDA-approved treatments in some cancers, although not ovarian cancer.

“We can imagine re-educating the fibroblasts and tumor cells with immune T cells after chemoresistance develops,” Zou says.

“Then we could potentially go back to the same chemotherapy drug that we thought the patient was resistant to. Only now we have reversed that and it’s effective again,” Liu adds.

To read this full article on News Medical, click here.

New Prevention Strategies For Ovarian Cancer Identified

New Prevention Strategies For Ovarian Cancer IdentifiedResearchers have found that knowing the early changes in the cells of the fallopian tubes of women carrying the genetic mutation responsible for ovarian cancer could open the way for new preventative strategies.

The study sought to understand why women with the BRCA1/2 mutations develop ovarian cancers and what happens in the cells where the cancers originate to trigger them.

The findings showed that in approximately 60 percent of women carrying the BRCA1 or BRCA2 gene, a radically altered subcellular activity occurred in the tubal cells that are closest to the ovary.

“These new findings take us a step closer to understanding how ovarian cancers develop in BRCA 1/2 gene mutation carriers, opening up new opportunities for ovarian cancer prevention,” said Martin Widschwendter, professor at University College London.

These sub-cellular changes were similar to those seen in cells from ovarian cancer specimens.

The changes were not seen in the women without BRCA mutations.

In addition, the researchers identified an enzyme (activation-induced cytosine deaminase, AID) that appears to trigger this re-programming.

“This is vital as at present the most effective method of prevention is drastic risk-reducing surgery, which deprives women of their hormones and their ability to give birth prior to the menopause,” Widschwendter added.

For the study, published in the journal Nature Communications, the team examined the post-surgical reproductive tubal tissue from 115 women, 56 with the BRCA1/2 mutation and a control group of 59 without.

They analysed the cells’ epigenetic programmes, the ‘software’ which dictates how the cells read instructions encoded within the DNA.

Also, they compared both ends of the Fallopian tubes (the fimbrial, closest to the ovary, and the uterine, closest to the womb), from the same woman.

“The next steps will be to investigate the merit of drugs that affect epigenetic reprogramming and to look for biomarkers which allow safe monitoring of the effect of such drugs,” Widschwendter concluded.

To read the full article on The Tribune, click here.

Ovarian Cancer Chemotherapy Resistance Is Growing: Why?

Ovarian Cancer Chemotherapy Resistance Is Growing: Why?

Ovarian cancer is a fear of most women, largely due to the abysmal prognosis once it is found. The reasons for this are clearly understood — the more advanced a cancer is when it is discovered, the more difficult it is to treat because it has spread through the lymphatic system. Because ovarian cancer has vague symptomatology, many women don’t recognize that there’s a problem until the cancer is quite advanced, meaning that the chances of long-term survival are very low.

The few symptoms that are associated with ovarian cancer include early satiety (or feeling full after eating just a small amount), bloating, constipation, vague abdominal discomfort, and occasionally nausea. These are symptoms that are prevalent in many other common disorders of woman as well, including gallbladder disease, irritable bowel syndrome, and food intolerances. The symptoms are often so slight that women may ignore them for many months until they get much worse, allowing the cancer to spread to local and sometimes even distant organs.

When discovered, ovarian cancer is often treated with surgery, radiation, chemotherapy, and, more recently, immunotherapy. Researchers at the University of Michigan in Ann Arbor say that adding immunotherapy to the patient’s treatment regimen allows them to avoid chemotherapy resistance, which is common in women with ovarian cancer and a reason that the prognosis is poor.

According to Tech Times, we have the scientific explanation about why chemotherapy doesn’t work for many people. Ovarian tumors contain two types of cells: cancerous cells and fighter cells. The bad cells are called fibroblasts, which can keep chemotherapy from working and make the entire tumor resistant to treatment, which worsens over time and with more chemotherapy. The good cells, immune T cells, reverse that process. T-cells are the workhorses of the immune system.

In a recent study of ovarian cancer tumors, physicians infused the platinum-based chemotherapy drug cisplatin in patients with ovarian cancer. During that study, scientists found that fibroblasts block platinum. That’s the reason platinum-based chemotherapy does not work, and women become immune to the treatment.

However, after infusing the tumors with T-cells, the tumors were once again susceptible to the chemotherapy, making it a plausible treatment. They hope that by combing T-cell therapy with cisplatin, many women may live longer and have a better quality of life. The study authors note that this holds high potential for women who are currently diagnosed with ovarian cancer and their treatment is stagnating or they are believed to be terminal.

Ovarian cancer can have genetic markers and is often associated with the BRCA-gene, which can run in families and make women vulnerable to breast cancer. Women who have first-degree relatives with breast or ovarian cancer should consider being tested for the gene. First-degree relatives include mothers, sisters, and children. Often, many women in a family will be diagnosed with breast or ovarian cancer, or both, throughout generations, so it is important to know family history. There are other risk factors for ovarian cancer, including obesity, being of African-American descent, and having never had children.

Some women with the gene decide to pre-emptively remove their ovaries, but it’s important to remember that decision causes surgical menopause, which can lead to other risks, such as heart disease. Women should be thoroughly counseled by an oncologist when they are diagnosed with ovarian cancer.

To read this entire article on Inquisitr.com, click here.

On the Scene at Annual Meeting: What Patients Need to Know

Gynecologic oncologists Leslie Randall, MD, of UC Irvine Health in Orange, CA, and Ginger Gardner, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, discuss some of the most important research presented at the 2016 Annual Meeting on Women’s Cancer in San Diego, CA, March 19-22. Ovarian cancer survivor and patient advocate Jocelyn Alfandre was a featured speaker at the Annual Meeting in a session about “Overcoming Barriers to Clinical Research.”

To view this video on YouTube, click here.

Ovarian 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.

Ovarian cancer is the leading cause of death from gynecologic cancer in the United States. Each year nearly 22,280 women in the United States will be diagnosed with ovarian cancer, and 14,240 will die. Ovarian cancer is sometimes called “the cancer that whispers,” because the disease often progresses before symptoms arise. Nine out of 10 ovarian cancers are epithelial ovarian cancers— deriving from the outer (epithelial) layer of the ovary.

The most important risk factor for ovarian cancer 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.

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.

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 1, grade 1 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 2, 3, and 4 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 2, 3, or 4 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.

A number of 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.

Immunotherapy For Ovarian Cancer 

Current immunotherapies for ovarian cancer fall into six broad categories: monoclonal antibodies; checkpoint inhibitors and immune modulators; therapeutic vaccines; adoptive T cell transfer; oncolytic viruses; and adjuvant immunotherapies. Most of 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.

Monoclonal Antibodies

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF), is FDA-approved for the treatment of ovarian cancer. Several monoclonal antibodies are currently being tested in clinical trials:

  • A phase II trial of farletuzumab that targets folate receptor alpha, which is highly expressed in ovarian cancer, in patients with low CA-125 platinum-sensitive ovarian cancer (NCT02289950).
  • A phase II study of mirvetuximab soravtansine (IMGN853) in patients with folate receptor alpha-positive advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer (NCT02631876).
  • A phase I study of mirvetuximab soravtansine (IMGN853) in patients with folate receptor alpha-positive advanced ovarian, primary peritoneal, or fallopian tube cancer (NCT02606305).
  • A phase I trial of mirvetuximab soravtansine (IMGN853) in patients with ovarian cancer that expresses folate receptor alpha (NCT01609556).
  • A phase I/II trial testing IMMU-132, an antibody-drug conjugate targeting Τrop-2, in patients with epithelial cancers (NCT01631552).
  • A phase I trial of DNIB0600A, an antibody conjugated to the anti-mitotic agent MMAE, for patients with platinum-resistant ovarian cancer (NCT01363947).
  • A phase I trial of DNIB0600A for patients with platinum-sensitive ovarian cancer (NCT01995188).
  • A phase I/II trial to test demcizumab (OMP-21M18), a monoclonal antibody targeting Delta-like ligand 4 (DLL4), an activator of the Notch signaling pathway (which is known to be important in cancer stem cells and cancer), in patients with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer (NCT01952249).
  • A phase I trial of monalizumab, targeting NKG2A receptors, in patients with ovarian, fallopian tube, and peritoneal cancer (NCT02459301)

Checkpoint Inhibitors and Immune Modulators

Another promising avenue of clinical research in ovarian cancer is the use of checkpoint inhibitors and immune modulators. 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.

  • Three phase II trials of pembrolizumab (Keytruda®, MK-3475), an anti-PD-1 antibody, in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancer (NCT02608684, NCT02440425, NCT02537444).
  • A phase I/II trial of durvalumab (MEDI4736), an anti-PD-L1 checkpoint inhibitor, in patients with recurrent ovarian cancer (NCT02484404).
  • A phase I/II trial of durvalumab (MEDI4736) and motolimod, a Toll-like receptor 8 agonist, for patients with ovarian, primary peritoneal, or fallopian tube cancer for whom doxorubicin is indicated (NCT02431559). This is sponsored by the Cancer Research Institute.
  • A phase I study of durvalumab (MEDI4736) and tremelimumab, a CTLA-4 checkpoint inhibitor, for patients with advanced solid tumors, including ovarian, primary peritoneal, or fallopian tube cancer (NCT01975831). This is sponsored by the Cancer Research Institute.
  • A phase I/II study to test nivolumab (Opdivo®), a PD-1 antibody, combined with INCB024360, an IDO1 inhibitor, in patients with advanced cancer, including ovarian, fallopian tube, or primary peritoneal cancer (NCT02327078).

Therapeutic Vaccines

Scientists have identified several ovarian cancer-associated 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 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 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.

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

  • A phase II/III trial of gemogenovatucel-T (Vigil™) for patients with stage 3/4 high-grade ovarian, fallopian tube, and primary peritoneal cancer (NCT02346747).
  • A phase II trial of TroVax® (MVA-5T4), targeting the 5T4 antigen, versus placebo in patients with relapsed asymptomatic ovarian cancer (NCT01556841).
  • A phase II trial of a dendritic cell vaccine for patients with advanced ovarian cancer (NCT00703105).
  • A phase I/II trial combining CDX-1401, which targets the NY-ESO-1 protein, epacadostat (INCB024360), an IDO1 inhibitor, and Poly-ICLC, a Toll-like receptor 3 stimulant, in ovarian, fallopian tube, or primary peritoneal cancer in remission (NCT02166905).
  • A phase I/II study of a dendritic cell vaccine for patients with advanced ovarian, fallopian tube, or peritoneal cancer (NCT02432378).
  • A phase I trial of CMB305 in patients with locally advanced, relapsed, or metastatic cancer that expresses NY-ESO-1, including ovarian cancer (NCT02387125).
  • A phase I study of a p53 vaccine for patients with ovarian, fallopian tube, or peritoneal cancer (NCT02275039).
  • A phase I trial of a vaccine given with Montanide and Poly-ICLC, a Toll-like receptor 3 stimulant, for patients with ovarian, fallopian tube, or peritoneal cancer ( NCT02452775).
  • A phase I trial in metastatic solid tumors, including ovarian cancer, of a vaccine targeting the HER2 antigen (NCT01376505).
  • A phase I trial testing ID-LV305, a vaccine targeting the NY-ESO-1 antigen, in patients with solid tumors, including ovarian cancer (NCT02122861).

Adoptive Cell Transfer

A fourth major avenue of immunotherapy for ovarian cancer is adoptive T cell transfer. In this approach, immune 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:

  • A phase II trial to test white blood cells genetically engineered to recognize NY-ESO-1 for patients with metastatic cancer (NCT01967823).
  • White blood cells genetically engineered to recognize NY-ESO-1, given along with dendritic cells pulsed with NY-ESO-1 antigen as a vaccine, in a phase II trial for patients with stage IV, advanced, or refractory malignancies (NCT01697527).
  • A phase I/II trial testing T cells genetically engineered to target the MAGE-A3 antigen in patients with ovarian cancer (NCT02111850)
  • A phase I/II study to test chimeric antigen receptor (CAR) T cell therapy targeting mesothelin, which is overexpressed in ovarian cancer, pancreatic cancer, and mesothelioma (NCT01583686).
  • A phase I/II trial to test T cells genetically engineered to target the MAGE-A3 or NY-ESO-1 antigens in patients with ovarian cancer (NCT01567891).

Oncolytic Viruses

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

  • A phase II trial testing a measles virus genetically enhanced to express the thyroidal sodium symporter gene (MV-NIS) in patients with ovarian, fallopian tube, or peritoneal cancer (NCT02364713).

Adjuvant Immunotherapies

Adjuvant immunotherapies are substances that are either used alone or combined with other immunotherapies to boost the immune response even more.

  • A phase I study of epacadostat (INCB024360), an IDO1 inhibitor, for patients with ovarian, fallopian tube, or peritoneal cancer (NCT02118285).

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

To read more about ovarian cancer and immunotherapy on CancerResearch.org, click here.

Scientists Explain Why Ovarian Cancer Becomes Resistant To Chemotherapy

Scientists Explain Why Ovarian Cancer Becomes Resistant To ChemotherapyThe reason why ovarian cancer becomes resistant to chemotherapy over a period of time has always fascinated and puzzled the researchers. Now, a team of researchers from the University of Michigan has come up with a possible reason.

According to study author J. Rebecca Liu, almost all patients respond to the chemotherapy treatment at first. However, all of them develop chemoresistance after some time. Liu further says that ovarian cancer is often detected during the late stages, which, in turn, makes treatment difficult. Chemoresistance, in addition to difficulty in treatment, makes it a pretty fatal form of cancer.

Ovarian cancer consists of two types of cells – good and bad. The bad cells called fibroblast stops responding to chemotherapy drugs. On the other hand, the good, or immune T-cells, help reverse that effect.

Researchers have always thought that chemoresistance occurs because of genetic alterations in the affected individual. However, the recent study proves that it is not the case.

During the study, the research team derived samples of affected tissue from ovarian cancer patients. The cells were isolated by their type, so that the researchers are able to see the environment of the cells in mice and humans and then correlate it with the actual prognosis.

The researchers also discovered that the fibroblasts tend to block platinum, which is often recommended as a part of the platinum-based chemotherapy drug cisplatin. Thus, the drug is unable to kill the cancer cells. On the other hand, the immune T-cells nullify the effect of the bad cells. Infusing immune T-cells into fibroblasts helps patients respond to the treatment as before.

The researchers, thus, suggest a combination of chemotherapy and immunotherapy for the treatment of ovarian cancer patients. That is, providing immune T-cells to the patients who have developed resistance against the treatment can help make chemotherapy effective again.

To read the full article on News Everyday, click here.

Precision Medicine Yields Better Outcomes for Patients in Phase I Clinical Trials

Precision Medicine Yields Better Outcomes for Patients in Phase I Clinical TrialsA meta-analysis of 346 phase I clinical trials involving more than 13,000 patients found that patients whose treatment was selected based on the molecular characteristics of their tumor had significantly better outcomes. The study was featured in a press briefing today and will be presented by Schwaederle et al Monday, June 6, at the 2016 ASCO Annual Meeting in Chicago (Abstract 11520).

“Our study suggests that, with a precision medicine approach, we can use a patient’s individual tumor biomarkers to determine whether they are likely to benefit from a particular therapy, even when that therapy is at the earliest stage of clinical development,” said lead study author Maria Schwaederle, PharmD, of the Center for Personalized Cancer Therapy at the University of California, San Diego, School of Medicine. “This strategy often results in good outcomes for patients, and I hope it will encourage and reassure doctors and patients considering enrollment in precision medicine–based phase I trials.”

About the Study

Previous meta-analyses of phase II and phase III trials by the same researchers observed similarly improved outcomes with precision medicine approaches. According to the authors, this is the first study to show that such benefits are apparent even at the first stage of clinical development. It suggests that tumor biomarkers should be increasingly used to select patients for phase I clinical trials.

The study examined efficacy and safety data from 346 phase I trials published between 2011 and 2013. The analysis included 58 treatment arms that employed precision medicine—defined as using biomarkers to select patients for treatment—and 293 that did not. (All but one of these precision medicine trials evaluated a targeted agent; that trial evaluated the chemotherapy drug topotecan, which is believed to inhibit hypoxia-inducible factor 1-alpha [HIF-1 alpha], and patients in that trial were tested for this marker.)

Key Findings

The researchers found that in treatment arms employing precision medicine, the tumor shrinkage rate was 30.6%, compared to 4.9% in those that did not. Patients in precision medicine arms also had a longer progression-free survival compared to other arms (median = 5.7 vs 2.95 months).

Results were similar in a subanalysis that included 57 trials of targeted therapies. In this group, treatment arms using biomarkers to assign patients to treatments had tumor shrinkage rates of 31.1%, compared to 5.1% for those that did not. Additionally, researchers found that matching patients to therapy based on genomic biomarkers resulted in a higher tumor shrinkage rate (42%) compared to protein biomarkers (22.4%).

In this analysis, the high tumor shrinkage rate and prolonged time to disease progression observed with precision medicine approaches suggest that phase I studies, which have traditionally focused on safety, can also provide important insights into efficacy and the patients likely to benefit most. Incorporating survival endpoints into phase I trials may help accelerate development of important new therapies, the authors suggested.

ASCO Perspective

Chair of ASCO’s Cancer Communications Committee Don S. Dizon, MD, FACP, remarked, “Precision medicine is not the future of cancer care—it is the present. This study reinforces that the more we personalize treatment to the patient and the tumor, the better the outcomes—even in the earliest phases of research. This is the same approach that ASCO’s TAPUR trial is using, and we anticipate it will also bring new insights that lead to better therapies for patients in need.”

This study received funding and support from the Joan and Irwin Jacobs Philanthropic Fund.

To read this entire post on AscoPost.com, click here.