How Immunotherapy Is Making an Impact in Ovarian Cancer

Among women, ovarian cancer is the fifth leading cause of cancer-related death, and is responsible for more deaths than any other cancer of the female reproductive system.  Last year, there were more than one million new cases of ovarian cancer worldwide and, in the United States, roughly 14,000 deaths due to ovarian cancer.

While all women are at risk for ovarian cancer, the odds of developing the disease increase as women age. The vast majority (>90%) of cases occur in women over the age of 40, and the greatest risk is found in women age 60 or older.

There are several types of ovarian cancer, with the most common being epithelial ovarian cancer, which arises from the epithelial cells of the ovary and comprises roughly 90% of ovarian cancer cases. In all types, once the cancer has metastasized, or spread from the ovary to other organs, the odds of survival are significantly lower. While patients with advanced ovarian cancers may respond initially to surgery, chemotherapy, and targeted therapy, many patients often see their cancers return, and nearly half these patients do not live beyond five years.

As a result, new strategies are urgently needed to improve ovarian cancer care and increase patient survival. Immunotherapy—a new class of treatments that help patient fight cancer with their own immune system—is one avenue that appears promising. The U.S. Food and Drug Administration (FDA) approved one immunotherapy for certain ovarian cancer patients whose tumors have the MSI-high biomarker. This small subset of patients is characterized by tumors that are heavily mutated. In addition, there are currently more than 220 active clinical trials that are evaluating a number of immunotherapies for patients with nearly all types of ovarian cancer.

To better understand the current immunotherapy landscape in ovarian cancer and how these immune-based approaches are starting to improve care for some patients, we spoke with Dmitriy Zamarin, MD, PhD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, NY, and a CRI Anna-Maria Kellen Clinical Accelerator investigator.

Arthur N. Brodsky, PhD:

Checkpoint inhibitor immunotherapies, especially those that target and block the PD-1/PD-L1 pathway, have been pretty successful for a number of cancer types. Where do they fit into the treatment landscape for ovarian cancer?

Dmitriy Zamarin, MD, PhD:

Some of the earlier trials testing checkpoint immunotherapy in small numbers of ovarian cancer patients seemed promising, but as we have gone through larger studies the response rate to these agents now appears to be fairly low, about 9 to 10 percent, regardless of which PD-1/PD-L1-targeting agent is used. So, at least by themselves, PD-1/PD-L1 inhibitors likely will not play a significant role in treating ovarian cancer.

Arthur N. Brodsky, PhD:

I know that in some other cancer types, these checkpoint immunotherapies have been combined with other treatments, like chemotherapy, to make them more effective. Is that approach being applied in ovarian cancer, too?

Dmitriy Zamarin, MD, PhD:

Definitely. There are a number of ongoing clinical trials in ovarian cancer, including in the upfront setting, meaning the newly diagnosed patients, where the standard chemotherapy drugs like carboplatin and paclitaxel are being combined with PD-1 or PD-L1 checkpoint immunotherapies. Some trials just use a combination of chemotherapy with these agents alone, but now a number of trials are starting to incorporate additional agents, such as bevacizumab, which is an antibody that targets tumor blood vessels via the VEGF pathway, and maintenance PARP inhibitors, which target tumors’ DNA repair capabilities.

Overall, there are a number of fairly large clinical trials that are currently exploring these combination regimens to see whether we can improve the cure rate for ovarian cancer—which hasn’t changed in 20 years—by using these drugs earlier in the course of treatment. Now, these drugs are also combined in more advanced settings, such as for patients who have had their first recurrence of ovarian cancer. In some of these trials, for example, patients receive platinum-containing doublet chemotherapies in combination with checkpoint immunotherapy.

There are also several trials ongoing in patients with advanced platinum-resistant ovarian cancer, including one combining a chemotherapy known as liposomal doxorubicin in combination with bevacizumab, in combination with atezolizumab (a PD-L1-blocking checkpoint immunotherapy), and in combination with both bevacizumab and atezolizumab.

Arthur N. Brodsky, PhD:

While the checkpoint immunotherapies targeting the PD-1/PD-L1 pathway are the most widely used today, there are others being used to block the CTLA-4 checkpoint pathway. In some cancer types, combination strategies that target the PD-1/PD-L1 and CTLA-4 pathways simultaneously have been shown to enhance the immune system’s ability to eliminate tumors. Has this combination shown any promise in ovarian cancer?

Dmitriy Zamarin, MD, PhD:

Yes. In one trial performed by the NRG oncology group, half the patients received a PD-1 immunotherapy alone and half received both PD-1 and CTLA-4 immunotherapies. While the first group had a response rate of 12 percent, which is what’s expected for PD-1 inhibitors alone, the combination group had a response rate of over 30 percent. There was also a doubling of the progression-free survival rate—from two months to four months—in the combination group.

Unfortunately, many of these responses were not necessarily that durable. So even with longer progression pre-survival, the majority of the patients eventually did progress. Clearly, even with this double combination, there is still further work that needs to be done.

Arthur N. Brodsky, PhD:

I agree, and think it highlights the importance of more basic research to better understand the biology behind these responses and why they don’t last as long as we’d like.

Now I want to turn to another type of immunotherapy—oncolytic virus therapy—that is currently being evaluated in ovarian cancer. These oncolytic viruses are used to infect tumor cells, which then burst and attract the attention of the immune system. In particular, you are leading a trial supported by the Cancer Research Institute (CRI) in which a modified adenovirus is injected directly into patients’ ovarian tumors. This oncolytic virus has also been engineered to cause the infected cancer cells to produce a molecule called GM-CSF, which helps promote immune activity. In addition to the oncolytic virus, patients are also treated with a PD-1 immunotherapy. Could you talk about this trial and the rationale behind it?

Dmitriy Zamarin, MD, PhD:

Absolutely. Unlike the name suggests, oncolytic viruses don’t just cause tumors to burst, but they also can activate the immune system and basically promote a vaccine-like immune response against the tumor. When we first tested these in animal models we also found that if we combined the oncolytic virus therapy with checkpoint immunotherapy, these two agents can really act in a synergistic manner.

This oncolytic virus is particularly suited to ovarian cancer because most cases of the disease are primarily localized to the peritoneal cavity. This allows us to deliver the virus directly to the tumor where the virus can infect the cancer cells, induce inflammation, and stimulate immune responses against these cancer cells.

The beauty of this strategy is that you don’t necessarily need to infect every single tumor cell. All you need to do is infect some tumor cells. The activation of immune responses against the infected tumor cells can promote tumor-specific T cells. We hope that these T cells can then act systemically and seek out and destroy cancer cells no matter where they are in the body. To help the T cells out, we also treat the patients with a PD-L1 inhibitor in the hopes it will allow these cancer-targeting T cells to overcome some of the resistance that tumors can develop to PD-1 or PD-L1 immunotherapy alone.

Arthur N. Brodsky, PhD:

I’m glad you brought up T cells. These are some of the most powerful immune cells in our body. As a result, many immunotherapies, checkpoints for example, seek to activate them against cancer. Another class of immunotherapies, known as cell therapies or adoptive cell therapies, also take advantage of these T cells. In general, they work by supplying patients’ bodies with an army of T cells that can target and eliminate their tumors. Are there any promising cell therapies being tested in ovarian cancer right now?

Dmitriy Zamarin, MD, PhD:

The field of cell therapy in ovarian cancer is still kind of early. To date, cell therapies have primarily been successful against “liquid” tumors, such as leukemia and lymphomas that arise from the blood. The development of cell therapies against solid tumors, like ovarian cancer, has been slower for several reasons. First, we don’t necessarily have a good target on the solid tumor cells for the T cells to recognize. Second, the tumor environment itself is harsh and might not be as permissive to these T cells in solid tumors as they are in liquid tumors. Nevertheless, there are a number of trials in ovarian cancer that are evaluating these adoptive T cell therapies.

One ongoing clinical trial is using CAR T cells, which stands for chimeric antigen receptor T cells. In this therapy, a patient’s normal T cells are taken from their body and then equipped with a synthetic CAR receptor that enables them to more effectively target cancer cells. The CAR T cells in this trial target a marker known as MUC16, which is very commonly expressed by ovarian cancer cells. Patients receive these CAR T cells both intravenously and intraperitoneally, which ensures the T cells are delivered directly to the site of disease. This was done because of some of the preclinical findings that suggested this kind of approach can work better. These CAR T cells are also armed to produce a molecule known as IL-12, which helps these them expand and persist.

Another cell therapy approach uses engineered T cells, where their natural T cell receptor is replaced with another T cell receptor designed to target cancer cells. One current trial is using this engineered T cell approach to target a protein called NY-ESO-1 and is being led by Dr. Kunle Odunsi of the Roswell Park Comprehensive Cancer Center.

Arthur N. Brodsky, PhD:

An important point to remember with these cell therapies is that they’re designed to target specific markers—also known as antigens—that are expressed by the cancer cells. Another way to stimulate immune responses against cancer-related targets is through vaccines, which basically educate the immune system and tell it what the cancer looks like. Then it can launch its own response and form its own T cells to go after the tumor. Are vaccines being explored against ovarian cancer, too?

Dmitriy Zamarin, MD, PhD:

Absolutely. Ovarian cancer was one of the first human cancers against which vaccines were used in the past. Most of the vaccine approaches to date have utilized antigens that are commonly expressed by ovarian cancers. These include cancer-germline antigens such as MAGE proteins, NY-ESO-1, and some others. Unfortunately, even though there has been a lot of evidence that patients develop immune responses against these targets after vaccination, these vaccines haven’t always led to clinical responses and tumor elimination. But these failures might not be because the vaccines aren’t effective. Rather, even if we are able to generate the T cells against these antigens, the T cells are not really able to function well within the harsh tumor environment that can suppress the activity of cancer-targeting T cells.

Instead, the best way to ensure that the vaccines are beneficial to patients might be to combine vaccines with other agents that modulate immune activity, whether it be checkpoint immunotherapies, certain chemotherapies, or maybe even a combination of them. At least one vaccine study has shown some promise. In this study, patient tumor samples were collected and basically “ground up” and then mixed with immune cells called dendritic cells. These dendritic cells are important coordinators of overall immune activity, and after they were exposed to the tumor tissue the immune cells were injected back into patients in combination with low dose chemotherapy.

The group that led this study at the University of Pennsylvania did see some very intriguing activity and the patients appeared to experience prolonged clinical benefit. So this is definitely attractive because as we’re vaccinating patients with samples of their own tumor tissue, we are essentially vaccinating them against their own mutated tumor antigens. So there’s certainly something to this strategy, and I look forward to seeing more of these kinds of approaches develop in the future.

Arthur N. Brodsky, PhD:

I want to turn back to the importance of the tumor environment. You’ve mentioned it’s not just enough to form an immune response and tell the immune system what the tumor looks like. It also needs to be able to go in and carry out the job once it actually gets to the tumor, which isn’t always easy. This seems like a big challenge that, if solved, could help improve care for more patients with ovarian cancer.

To that end, what do you think are some of the biggest challenges or the biggest unanswered questions that can help guide future strategies against ovarian cancer?

Dmitriy Zamarin, MD, PhD:

One of the biggest challenges is that we still don’t understand why certain patients respond to immunotherapy versus patients that do not. The biomarkers that have been somewhat successful in other cancer types, such as tumor mutational burden or PD-L1 expression, have not really been that promising in ovarian cancer so far. As a result, we cannot use these biomarkers to guide our thinking in the clinic. In the future, given the wide variety of immune-based strategies in development, we will need biomarkers to help guide treatment-related decisions and ensure that each patient receives the therapy that is most likely to work for them.

Another significant challenge in ovarian cancer is the marked heterogeneity that we see both within individual tumors as well as from one tumor to another. This means that the tumor cells can differ significantly in their identity and biological activity. So if we take a newly diagnosed ovarian cancer patient and then resect every single tumor that they have, and then look at the tumors under a microscope, we can find quite a variety of different tumor environments even within the same patient.

Some ovarian tumors have a lot of immune cells and are clearly very well-recognized by the immune system. Other tumors are completely cold, meaning that they somehow found a way to escape from the immune response. And this is within the same patient, which makes it very difficult to develop biomarkers because most of the biomarkers are based on a biopsy of a single tumor that a patient would receive prior to getting immunotherapy. So if we biopsy the “wrong” tumor, we could be misled by both the environment that we see within the tumor and sometimes the actual tumor genetics.

The main challenge that we face is the lack of general understanding of what is generating the different types of tumor environments in ovarian cancer. Furthermore, we need to learn how we can track the different types of environments to see whether we can identify the patients who are more or less likely to respond to checkpoint immunotherapy. Of course, we also need to know how to overcome the immune-suppressing effects within each of these types of tumor environments. That will be a key solution to the development of effective immunotherapy strategies for this disease.

Arthur N. Brodsky, PhD:

Finally, throughout this conversation we’ve been discussing a number of different types of immunotherapy approaches, and it might not have been clear that all of these are being evaluated in clinical trials. Unfortunately, there seem to be lot of misconceptions regarding clinical trials out there, and perhaps it’s leading to patients not necessarily understanding how valuable these clinical trials can be. So could you explain the importance of clinical trials, and how they can help both the patients themselves and the advancement of the field as whole?

Dmitriy Zamarin, MD, PhD:

Yes, there is a great misconception out there that clinical trials are for patients that have failed all standard lines of therapy. This is very untrue, and is unfortunately what we encounter very often with a patient who has already received five, six, seven lines of therapy and now has no therapeutic options left. These patients come to us to try to enroll onto a clinical trial, and most end up not being eligible for clinical trials for several reasons. They may be already too sick, since they have received so many lines of therapy and the cancer has progressed, or they may have already received the chemotherapies that are being tested in combination with novel agents. Just by receiving these chemotherapies in the past they may be excluded from the trial.

Another important point to mention is that clinical trials have the potential to benefit patients very early on, not just at the very late stages of disease. The goal of clinical trials is to increase the number of cures, as opposed to just prolonging the time to recurrence, so it’s certainly worth enrolling on these trials even if a patient is very early in their diagnosis. In ovarian cancer, for example, the average recurrence rate is 80 percent or higher for any newly diagnosed advanced ovarian cancer patient. That’s why they might want to consider enrollment on a trial that can potentially decrease the risk of cancer coming back. Even if it’s able to decrease this risk by just 10 percent, that would be important, because it could benefit a significant number of patients, especially if the treatment eventually becomes approved.

So I would highly encourage patients to seek out clinical trials at every stage of their treatment. Being on a clinical trial does not necessarily mean that you cannot receive standard therapy and you will only be treated with an experimental drug by itself.  Sometimes experimental drugs are combined with standard therapy to make it better. Whenever a treatment decision needs to be made, I think clinical trials are something that the patients should discuss with their physicians.

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