Immunotherapy Has Big Potential In Ovarian Cancer Treatment

Immunotherapy Has Big Potential In Ovarian Cancer TreatmentEarly studies are showing promise for immunotherapy agents such as checkpoint inhibitors in the treatment field of ovarian cancer, according to Jonathan Ledermann, M.D.

One such study is JAVELIN Ovarian 200, a study of Bavencio (avelumab) alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer. This phase 3 global study is currently ongoing (NCT02580058).

Additionally, checkpoint inhibitors in combination with PARP inhibitors are garnering interest, with the impact of PARP inhibitors already well established in this tumor type.

In an interview with CURE during the 2017 ESGO Congress, Ledermann, professor of medical oncology, UCL Cancer Institute, London, United Kingdom, discussed the promise of immunotherapy in ovarian cancer and emphasized the importance of participation in clinical trials.

What is the status of immunotherapy in the treatment of patients with ovarian cancer?

To summarize, there are now single-agent studies with four of the checkpoint inhibitors that have been tested in ovarian cancer. At the moment, we are still at a very early stage in understanding the data. Only one of those [trials] has been published; the others have been presented.

One of the reasons that the results are slow coming forward is because we do need to follow these patients for a period of time. No longer can you use surrogate markers such as tumor response to give us an indication that these drugs are active—actually, the response rates are not that high. Therefore, we have to look at the length of disease control, progression free-survival and perhaps even overall survival to get a feeling of whether these agents will be helpful for these patients. That is why we don’t have those data yet.

Having said that, the next wave of trials is well underway and some have already completed. One is combining chemotherapy and/or Avastin (bevacizumab) with checkpoint inhibitors. Now, there are some scientific theoretical and circumstantial evidence to suggest that either chemotherapy, Avastin or both, benefit the activation of the immune system. After all, this is what these drugs are doing—activating the host’s immune system. If you can improve the immune environment in the tumor, you may help the activation of the immune system. That is what the rationale is of adding cytotoxic drugs or Avastin to the milieu. However, of course, it is a big undertaking, and an expensive undertaking. Yet, there are a number of trials combining those agents with checkpoint inhibitors.

There is also some early work going on with combining checkpoint inhibitors with other molecularly targeted therapies, particularly PARP inhibitors. There are some data to suggest that the combination of PARP inhibitors and checkpoint inhibitors will enhance the antigen expression and the immune activation. Therefore, those phase 1/2 trials are ongoing. People are now talking about launching larger randomized trials, which is interesting considering we haven’t seen some of the early data yet. That just shows the interest and the head of steam that checkpoint inhibitors have in ovarian cancer.

Is it too early to tell if either PARP inhibitors or chemotherapy will be more effective combined with immunotherapy?

It is too early to tell. However, the first combination with chemotherapy, the JAVELIN Ovarian 200 study, has finished recruitment. We are very eager to hear those data, but that will be probably another nine to 12 months. That will be the first point in this combination with chemotherapy.

Combinations with other drugs, such as Avastin or PARP inhibitors, are way behind. Although some randomized trials have started, it is going to be a long time before we know the activity of those drugs.

What would your advice be on approaching immunotherapy in ovarian cancer with such little data?

My advice would unequivocally be to enroll patients in clinical trials. We should not be dabbling around and giving immunotherapy to everyone when we really don’t understand which drugs are active in which patients. For example, we know very little about the predictive factors for response. It is important that, as clinical academics, we encourage the industry to study what is happening in the tumors within the immune environment. How is it changing with these drugs, especially with chemotherapy? What is changing when you add bevacizumab?

We must understand what it is that make some patients benefit quite well and others not at all. This could be simple things, such as measuring PD-1 and PD-L1. Is it an oversimplification? It certainly could be in the field of ovarian cancer, but possibly other cancers, as well.

To read this entire article on CureToday.com, please click here.

Advertisements

New Drug Discovery Program Identifies Potential Treatments for Ovarian Cancer, Other Diseases

New Drug Discovery Program Identifies Potential Treatments for Ovarian Cancer, Other DiseasesResearchers have developed a new computer program, known as DrugPredict, to find new therapeutics for unmet diseases, like ovarian cancer, among medications the U.S. Food and Drug Administration (FDA) has already approved for other indications.

The program predicted and researchers later confirmed that the pain medicine Indocin (indomethacin) – alone or combined with chemotherapy drugs – killed patient-derived ovarian cancer cells.

Their study, “Using a novel computational drug-repositioning approach (DrugPredict) to rapidly identify potent drug candidates for cancer treatment,” appeared in the journal Oncogene. It details DrugPredict’s success in finding new disease targets for old drugs.

At present, more than 70 percent of women die within five years of being diagnosed with epithelial ovarian cancer. Since developing new drugs is a long, costly process, researchers at Cleveland’s Case Western Reserve University School of Medicine developed the DrugPredict program to match FDA-approved medications for new therapeutic indications.

“Traditional drug discovery process takes an average of 14 years and billions of dollars of investment for a lead anti-cancer drug to make the transition from lab to clinic,” the study’s first author, Dr. Anil Belur Nagaraj, said in a press release. “Drug repositioning significantly shortens the long lag-phase in drug discovery and also reduces the associated cost.”

The DrugPredict program cuts that phase by scanning a database of drugs of approved FDA therapies to treat specific conditions. It then matches the drug’s profile to other conditions against which it may also be effective.

The program incorporates what is known about a treatment — mechanisms of action, clinical efficacy and side effects — and matches it to targets of new diseases, such as ovarian cancer.

“For any given disease, DrugPredict simultaneously performs both a target-based and phenotypic screening of over half a million chemicals, all in just a few minutes,” said Dr. Rong Xu, the study’s co-lead author and associate professor of biomedical informatics at Case.

In the Oncogene study, DrugPredict generated a list of 6,996 chemicals that could potentially target ovarian cancer, at the top of which were 15 FDA-approved therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) were very high on the list, so researchers used laboratory experiments to confirm the computer program’s findings.

Indocin, a NSAID, killed patient derived drug-resistant and drug-sensitive epithelial ovarian cancer cells in vitro. Most importantly, cancer cells resistant to the common chemotherapy drug Platinol (cisplatin) were particularly sensitive to indocin. In fact, combining chemo drugs with indocin increased the death rate of cancer cells.

“By combining my laboratory’s expertise in ovarian cancer biology and Dr. Xu’s expertise in bioinformatics, we were able to uncover a potentially novel drug approach to treat ovarian cancer,” said co-lead author Dr. Analisa DiFeo, an ovarian cancer researcher at Case.

The next step is to test the effectiveness of indocin against ovarian cancer stem cells in a Phase 1 clinical trial. This will be done in collaboration with Dr. Steven Waggoner, division chief of gynecologic oncology at Cleveland’s University Hospitals Seidman Cancer Center.

To read this full article on Ovarian Cancer News Today, please click here.

Researchers Are Closer To A Screening Test For Ovarian Cancer

Researchers Are Closer To A Screening Test For Ovarian CancerA newly studied blood test could be the answer to a serious question: How can a woman tell if she has ovarian cancer in its earliest stage?

Currently, there are no approved screening techniques from the Food and Drug Administration to check for the disease.

The major concern is that early symptoms of ovarian cancer, such as bloating, pelvic or abdominal pain, feeling full quickly or urinary symptoms, often are missed or don’t show until the disease has advanced — lowering the survival rate for patients.

Researchers from Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston, created a technique to detect ovarian cancer early and accurately.

“Seventy percent of patients come to the clinic with stage 3 or stage 4 ovarian cancer and the cure rate for those patients is below 30 percent,” said Dipanjan Chowdhury, Ph.D., chief of the Division of Radiation and Genomic Stability in the Department of Radiation Oncology at Dana-Farber, in an interview with CURE. “But if you get to the clinic when it is stage 1, then the cure rate is over 92 percent.”

This blood test could be a major breakthrough for people who are concerned about ovarian cancer. The two most common tests used now to detect the disease are ultrasounds and a CA-125 — a protein in the blood that often shows up in high levels in women with ovarian cancer — blood test. But, according to the American Cancer Society, studies using both tests for screening of women at average risk of disease led to more testing and sometimes more surgeries, but did not lower the number of deaths caused by ovarian cancer.

In this recent study — made possible through the support of Tina’s Wish Foundation and the Deborah and Robert First Family Foundation — published in the scientific journal eLife, the researchers explained how they identified a network of circulating microRNAs — small, non-coding pieces of genetic material — that are associated with risk of ovarian cancer and can be detected from a blood sample.

Among 454 patients with a variety of diagnoses, the blood test had 100 percent specificity for ovarian cancer, meaning that very few patients had a false positive. Additionally, the non-invasive test outperformed CA-125 and functioned well regardless of patient age, histology or stage, noted the authors.

“We might now have a blood test that allows us to detect ovarian cancer,” said Chowdhury, senior author on the study. “CA-125 has proven to be inadequate to detect ovarian cancer. It’s a test that, when you have the disease, it is good to help monitor. A diagnostic could make a huge difference in survival rates. This is a blood test that has potential to be an early diagnostic tool for ovarian cancer.”

Although this test is very exciting for researchers, Chowdhury said it is still years away from being used as part of regular screening. “It’s proof of concept that this may work, but we do not have a test yet,” he said.

Chowdhury’s long-term goal is to have the blood test be part of an annual physical for women, much like prostate-specific antigen, or PSA, testing that men undergo to check for prostate cancer. Women would go before they show symptoms.

However, for people who are considered high-risk because of family history, such as if they are BRCA-positive, he sees this test being implemented in the near future.

Chowdhury anticipates two next steps in order to further the research and accuracy of the blood test.

One is to examine the blood test in samples of those who are at higher risk because of family history. These samples are from Dana-Farber. He said they will try to determine if some people within a family are much more prone to getting cancer than others.

Then, in samples that were collected from studies run by the National Cancer Institute (NCI), Chowdhury and colleagues will be testing the samples blind.

“This means that we don’t know which samples are from people who eventually became patients with cancer,” said Chowdhury.

They will then send the data to the NCI. Those researchers will match it and let Chowdhury’s team know how accurate their predictions were. “The goal is to really come up with a test that can predict cancer years before it’s obvious,” Chowdhury said.

To read this full article on CURE, please click here.

Survival Predictors in Ovarian Cancer and Current Immunotherapeutic Strategies

The evidence for immune checkpoint inhibitors as treatment for patients with ovarian cancer is growing, with several studies demonstrating durable and complete tumor regression in chemotherapy-refractory disease, according to an oral presentation given at the 35th Annual Chemotherapy Foundation Symposium in New York.1

Bradley J. Monk, MD, FACS, FACOG, discussed several immunotherapeutic approaches currently being explored and utilized for the treatment of ovarian cancer. Researchers have identified 3 major predictors for survival, which include tumor infiltrating leukocytes (TIL), programmed death-ligand 1 (PD-L1) expression, and mutational burden.

Although the presence of TILs at time of newly diagnosed ovarian cancer was found to be the most important prognostic factor for improved survival (hazard ratio [HR], 2.24; 95% CI, 1.71-2.92), in a prior study only 55% of tumor samples had TILs. PD-L1 expression is another major prognostic factor, but it is only identified in approximately 68% of patients. High levels of PD-L1 expression in ovarian cancer not only lead to poorer overall survival (OS) outcomes, but negatively affect progression-free survival (PFS) as well. Mutational burden is typically low in ovarian cancer.

Monotherapy with anti-PD-1 agents, such as nivolumab and pembrolizumab, only result in a 10% to 15% response rate among patients with ovarian cancer. One of the treatment challenges with checkpoint inhibitors for patients with ovarian cancer moving forward is increasing the amount of TILs, and thus immunogenicity, in tumor cells.

Previous studies have demonstrated that chemotherapy is immunogenic and enhances antigen presentation, immunogenicity, and increases cell susceptibility to immune attack. Pegylated liposomal doxorubicin (PLD) and carboplatin plus paclitaxel have demonstrated clinical efficacy in animal studies.

PARP inhibitors (PARPi) (eg, olaparib, rucaparib, niraparib) cause genomic instability and increase immunogenicity through an increase in mutational burden, neoantigens, and eventual PD-L1 expression and increased TIL. Researchers believe that combing PARPi and checkpoint inhibitor combinations may have a synergistic effect.

Moving forward, Dr Monk stressed that the identification of appropriate biomarkers is a crucial step. He concluded “Microsatellite instability and BRCA status are promising biomarkers, but further investigation in ovarian cancer is needed.”

Read more of Cancer Therapy Advisor‘s coverage of the Chemotherapy Foundation Symposium (CFS) by visiting the conference page.

References

Monk BJ. Elucidating a role for immunotherapy in ovarian cancer. Oral presentation at: 35th Annual Chemotherapy Foundation Symposium. November 8-10, 2017; New York, NY.

To read this full article by CancerTherapyAdvisor.com, please click here.

Survival Benefit Not Enough to Justify Centralized Ovarian Cancer Care

Survival Benefit Not Enough to Justify Centralized Ovarian Cancer CareOne in five patients with ovarian cancer said that they would not be willing to travel an additional 50 miles for cancer care for only a 6% 5-year survival benefit, according to the results of a study published in Gynecologic Oncology. However, the majority of surveyed women required a 5-year survival benefit of 6% or less to justify the additional travel.

“The women most likely to face this tradeoff are the 9% of the United States population living in counties > 50 miles distant from the closest gynecologic oncologist and the 15% of the United States population living in a Hospital Referral Region without a gynecologic oncologist,” wrote David I. Shalowitz, MD, of the department of obstetrics and gynecology at Wake Forest University in Winston-Salem, North Carolina, and colleagues. “These low-access regions of the United States should therefore be the first to benefit from interventions to 1) decrease the burdens of travel for women with ovarian cancer, 2) extend high-volume cancer care networks to underserved areas, including virtual and in-person outreach by gynecologic oncologists, and 3) improve the quality of the clinical care infrastructure at lower-volume cancer centers.”

Because patients with ovarian cancer have better clinical outcomes when treated at high-volume institutions, some have called for a centralization of ovarian cancer care at these centers. To determine how women would balance survival benefit against this additional travel to centralized treatment centers, Shalowitz and colleagues conducted a cross-sectional survey of women presenting to one of two clinics with a pelvic mass between February 2015 and 2016. Participants completed two discrete choice experiments, assessing the 5-year survival benefit required to justify 50 miles of additional travel, and the additional distance patients would travel for a 6% 5-year survival benefit.

The study included 62 participants, of whom 81% required a 5-year survival benefit of 6% or less to justify the additional 50 miles of travel. These participants were less likely to be employed (56% vs 83%; P = .05) and more likely to rate their health as good to excellent (86% vs 50%; P = .04) compared with those unwilling to travel this distance for the benefit.

Similarly, 80% of the participants said that they would travel 50 miles or more for a 6% survival benefit at 5 years. Almost half of the participants (47%) said that they would travel at least 250 miles for a 5-year survival benefit of 6%.

“We were unable to identify any significant demographic, geographic, or psychosocial differences between the groups of participants willing to travel an additional 50 miles for a 6% improvement in 5-year survival and those unwilling to travel, though at least one discrete choice experiment suggested that patients who are healthier, not currently employed, and less connected to their local neighborhood may be more willing to travel greater distances for care,” the researchers wrote. “Larger-scale study of cancer patients’ willingness to travel for care may reveal predictive characteristics not captured in this study; however, it is possible that willingness to travel is not reducible to other measurable factors.”

To read this entire article by Cancer Network, please click here.

2 Ovarian Cancer Survivors, 1 Shared Passion

2 Ovarian Cancer Survivors, 1 Shared PassionAnne Hermiller and Sarah Ludinich experienced ovarian cancer at different stages in life. What’s similar is their passion for making other women more aware of the disease and its effects.

Hermiller, of Findlay, learned she had cancer in 2014. “I was tired,” she said. “I was just getting tired.”

She went to a bed one night and just felt “a little bump,” which she thought was likely a hernia.

That bump turned out to be “a big mass,” and she sought treatment at the James Cancer Hospital in Columbus, where a surgery removed three tumors. There was one on each ovary — the size of a grapefruit and the size of a canteloupe — with a third in her abdomen, the size of a peach. It was stage 3-C, meaning the cancer had jumped from one part of the body to another.

Dr. Henry Gerad, medical oncologist with Blanchard Valley Health System, said only about 15 percent of ovarian cancer patients are diagnosed in early stages.

“We do not have very good screening techniques for ovarian cancer,” he said.

Symptoms may include abdominal bloating, pain, a change in bowel habits and fatigue. Gini Steinke, executive director of the Toledo-based nonprofit organization Ovarian Cancer Connection, said warning signs can also include difficulty eating, urgency or frequency of urination or back pain. These are usually caused by something else, but if it’s unusual for you and lasts more than two weeks, “get it checked out.”

“Women really need to be aware of their bodies,” she said.

She said ovarian cancer is “on the rise” in northwestern Ohio and southeastern Michigan, particularly among younger women and even teenage girls. She plans to have survivors educate medical and nursing students, so they are aware that what may seem to be a urinary tract infection or the flu might be something else.

Women who had their first child over age 35, have a history of another malignancy such as breast or colon cancer, or have the BRCA gene mutation are particularly at risk. Older women, women with polycystic ovary syndrome or endometriosis, and smokers may also be more at risk.

Ludinich knew “something wasn’t right.” She’d had bowel problems, felt bloated all the time and could only eat a few bites at a sitting — because, she later learned, the tumor was taking up so much space. But, she said, every woman experiences symptoms like bloating at some point.

It wasn’t until she actually felt a mass that she got it checked out. An oncologist at the James removed a basketball-sized tumor on Dec. 12, shortly after she turned 21. She had 28 treatments of chemotherapy beginning in January and was deemed cancer-free in April.

Hermiller put it this way: Think of how long it takes for a baby to show, when a woman is pregnant. “There’s so much room in there.” So, as a tumor grows, it isn’t always noticed.

Hermiller said many women don’t realize that “a Pap does not detect ovarian cancer.” (It actually screens for cervical cancer.)

And, “reproductive health is such a taboo subject,” Ludinich said. “We talk about breasts all the time now,” but we don’t talk about ovaries or uteruses, even though every woman has them, she said.

‘You Just Hold Your Breath’

Ludinich has a family history of other types of cancer, but not this kind. She called it “dumb luck.” One of her eggs started growing as if it was a fertilized egg about to become a baby. It’s known as germ cell cancer, different from epithelial cell, which is another type of ovarian cancer.

Being diagnosed “was, I mean, life-shattering,” she said. The day before, Ludinich was worrying about her classes at the University of Findlay, where she is majoring in physical therapy. Now she was making major medical decisions at 21. She said everyone knows someone who has had cancer, but for most of her friends in college it was a parent or a grandparent — not someone their own age.

Hermiller, now 56, was 53 when she was first diagnosed. She has no family history and was a “Y-rat,” meaning she worked out all the time, six times a week, at the YMCA. She also participated in 5Ks. She was a nonsmoker, watched her diet closely and had her children when she was young.

“It does not discriminate,” she said of ovarian cancer.

She had chemotherapy after surgery, also at the James. “I lost my long blond hair,” she said.
Hermiller said doctors had removed all the cancer, and things were looking good. Then she had a recurrence last summer. They ended up having to take out 18 inches of her lower intestine, and got “all but one little spot.” She had complications after the surgery, which might have been caused by something like a staple leaking after they readjusted how her organs lay in her body.

This necessitated a second, emergency surgery.

A year later, she is “struggling.” She lost a lot of weight, and can’t seem to put it back on. “And I’m tired all the time.” She’s also “obsessed with knowing my CA-125,” an antigen measured in a blood test.

Hermiller said she is “hopeful” that she will keep responding well to treatment. She has regular checkups every two months and said “you just hold your breath” when they come in the room.

She’s disappointed there isn’t much awareness of ovarian cancer, but she wasn’t very aware herself, before. She said we all take for granted “that it happens to somebody else.”

To read this entire article by The Courier click here, please.

New Techniques Give Survivors Hope

By: Annette McElhiney

Plasma beam that blasts ovarian cancer: Lightsaber surgery lowers the risk of healthy cells being destroyed and patients needing a colostomy bag  Read more: http://www.dailymail.co.uk/health/article-5010435/Plasma-beam-blasts-ovarian-cancer.html#ixzz4yRHoJxpw  Follow us: @MailOnline on Twitter | DailyMail on FacebookThose of us who have ovarian cancer are always on the look out for a treatment that will destroy all cancer cells without harming the other cells in our bodies. Therefore, the title of a recent article in a UK newspaper, the Daily Mail, caught my eye “Plasma beam that blasts ovarian cancer: Lightsaber surgery lowers the risk of healthy cells being destroyed and patients needing a colostomy bag

In this article, the writer Pat Hagen tells the story of a woman who avoided a colostomy because her doctor used a plasma beam. Hagen explains that in the past a technique using Diathermy (using extreme heat created by high-frequency electric currents to destroy unhealthy tissue) could be used and stated, “However, this [technique] also damages healthy cells deep inside the tissue as the heat passes from the probe and through the layers of cells underneath. In the bowel this increases the risk of doing so much damage that a stoma is required.”

Hagen continued on to say, “Over the last couple of years we have been trialling PlasmaJet. At the press of a button, the machine generates a bright beam of energy, similar to a Star Wars lightsaber, through the tip of a wand. Plasma is a form of energy generated using a gas called argon.”

This technique sounds like a dream come true. Consequently I did a little research on this technique and according to Wikipedia,“A particle beam (sometimes plasma beam, or charged particle beam) is an accelerated stream of charged particles such as electrons and protons, often accelerated towards the speed of light. In the laboratory, such beams are created by particle accelerators such as cathode ray tubes, cyclotrons, and the dense plasma focus. In nature, particle beams are created by electric fields (which accelerate charged particles in opposite directions), such as those in double layers and Birkeland currents.”

As early as 2012, researchers were studying how to use this technique to treat leukemia patients. Halleh B. Batch wrote in Inside Science, “We have a really amazing device. We can generate a beam of plasma that is around room temperature. It doesn’t burn anything; it doesn’t destroy or poke holes. You can touch it with your hand.”

Certainly this was a breakthrough. However, the treatment of solid tumors (like ovarian cancer), often lags behind that of blood cancers. So, what other studies have documented progress?

Stephen Chen of the South China News said about the plasma beam, “However a major obstacle to its use in clinical applications has been a lack of understanding of the underlying mechanism: were the cancer cells killed by physical forces such as heat, ultraviolet radiation and charged particles generated by the plasma, or “poisoned” by chemicals created in reactions with the plasma, such as hydrogen peroxide, ozone and nitrate ions?”

Chen writes, “Some current plasma guns vaporize cancer cells with power, but new research by a team led by Xia Weidong of the University of Science and Technology of China and Paul K. Chu of the department of Physics and Materials Science at City University of Hong Kong has shown that this approach may not always be necessary.”

Chen elaborates by saying in Scientific Reports that the researchers found a relatively gentle plasma beam could in some cases cause enough chemical reactions in a cancer cell to kill it.  They put water under plasma radiation for some time until it contained chemicals generated by the plasma, including ozone and nitrate ions, and then observed the action of the water on a common protein known as lactate dehydrogenase enzyme. They found the result was almost the same as putting the protein directly under a plasma beam.

This study certainly contributed to what they are doing now with the plasma beam as described in the recent article from the Daily Mail.

Hagen writes, “Over the last couple of years we have been trialling PlasmaJet. At the press of a button, the machine generates a bright beam of energy, similar to a Star Wars lightsaber, through the tip of a wand. Plasma is a form of energy generated using a gas called argon.”

He explains, “It’s different from most surgical lasers, which are generated by light or by carbon dioxide gas, which penetrate much deeper into the tissue — up to 14mm, compared with less than 2mm for PlasmaJet. The probe does not make contact with the tissue. It is held about 1cm above the area that needs treating and produces a beam of hot plasma gas that is fully absorbed by the cancerous cells on the surface, not the healthy cells underneath.”

According to Hagen, the use of this technique could save 50 percent of patients from having a colostomy.

So while this technique will not help all ovarian cancer patients, it suggests an advancement in the treatment that all survivors are hoping for.