Globally, ovarian cancer is diagnosed in an estimated 300,000 women each year—and another 570,000 are diagnosed with cervical cancer and 382,000 with uterine (endometrial) cancer. While significant advances have been made in surgical and chemo-based treatments for ovarian cancer, the survival rates have only modestly improved. Immunotherapy for ovarian cancer shows tremendous potential for addressing this devastating disease. In this session, Dr. Dmitriy Zamarin, medical oncologist at Memorial Sloan Kettering Cancer Center, will discuss details of immunotherapy clinical trials in ovarian cancer currently underway and take your questions about new treatments in gynecologic cancers.
Tamron Hall: Welcome back, and for those of you joining us for the first time, welcome to the 2021 Cancer Research Institute Virtual Immunotherapy Patient Summit. Now it’s time to learn about the latest immunotherapy progress in treating ovarian cancer, sometimes called the silent killer. This type of cancer can go undetected for far too long before it’s too late for help from traditional treatments. In this session, we’ll ask, “What can immunotherapy offer?” Joining us is Dr. Dimitriy Zamarin from Memorial Sloan- Kettering Cancer Center in New York City. There, he specializes in the care of women with gynecologic cancers, including cervical, ovarian and endometrial cancers. Dr. Zamarin, Arthur, thank you for being with us today.
Dr. Dmitriy Zamarin: Thank you, Tamron, for the introduction. Hello, everybody, and welcome to the CRI Virtual Summit. My name is Dmitriy Zamarin. I’m a medical oncologist at the Memorial Sloan-Kettering Cancer Center. I care for women with gynecologic cancers, including ovarian cancer, and I specifically conduct clinical trials in the field of cancer immunotherapy, which is, of course, what this whole summit is about.
So over the next few minutes, I would like to cover what exactly immunotherapy is and some of the recent strides we have made, at least in the field of ovarian cancer. So let’s get started. All right. So this is just a basic slides basic slide about the types of immunotherapies that are currently being utilized, or rather being tested, in ovarian cancer. Before going into the details, I want to
first specify what exactly immunotherapy is, and immunotherapy is using your body’s natural ability to recognize and kill cancer cells. There is a specific type of immune cell that we focus on whenever we give patients drugs that are called the immunotherapies, and that immune cell is called a T-cell. It is a cell that has been designed if you want to call it that way to recognize any sort of foreign invaders in your body. So, for example, bacteria viruses are recognized as foreign. They activate these T cells that are thought to specifically recognizing kill the cells that are infected with these agents, but T cells also have an ability to recognize the cancer cells as foreign and to kill them as well, and recently, or at least over the past few years, there has been an emergence of therapies that are targeting these T cells to teach them to recognize and kill cancer cells. So what types of therapies are we talking about? So in ovarian cancer and actually many other cancer types, we have a therapy called adoptive T-cell therapy. What does that mean? This is a type of therapy where the T cells are actually removed from your body. They’re taught in one way or another to specifically recognize something that’s expressed by the cancer cells. Then they’re infused back into the patients, and this kind of strategy has shown to be effective, I guess, against certain cancer types such as lymphomas and leukemias, and is currently being experimented on in patients with ovarian cancer and other gynecologic malignancies. The next thing I have here on this slide is bispecific antibodies. It’s sort of a complicated term, but antibodies are proteins that are naturally produced in the human bodies. But these proteins can also be engineered in the lab, and what bispecific antibodies do is that they can act as an anchor. They can specifically take any T cell and link it together with the cancer cell, effectively providing this anchor. So if you can imagine if we infuse a patient with bispecific antibodies, they can take the T-cells directly from the bloodstream, bring it to the door and teach that T-cell to kill the tumor cell.
There’s also neoantigen vaccines. As you can imagine, vaccines are substances that we can give to patients and teach their endogenous T-cells or T-cells that are already present in the patient to recognize some type of an antigen, an antigen being a protein that may be expressed by the cancer cells. So in the same way that the vaccines work against infectious diseases such as COVID, for example, vaccines can work against cancer. We have the substance or protein that that’s given to the patient. That protein teaches the T-cells to recognize the protein and then the T-cells then migrate to the side of the tumor, where they can kill off the cancer cells.
And lastly, an important thing to mention is that we would like to identify the biomarkers or predictors that could help us select the patients that are more or less likely to respond to immunotherapies, and that’s why the field is right now.
You can see that what has been successful or not being successful and sometimes we use award. Or battle analogy here and so far, the T-cells, or least the first-generation T cells that have been used have not necessarily been as effective against solid tumors such as ovarian cancer. But with the advent of technologies and the ability to engineer the T-cells to become better killers, we can now make better T cells that are stronger. First, the stronger and recognizing cancer cells, but also stronger killers of those cancer cells and some of the current strategies or clinical trials that are ongoing really exploring these next generation T cells.
And finally, as I mentioned on the first slide, we would like to develop the personalized medicine or the immune report card that can help us identify the patients that are more likely to benefit from one type of therapy or another. That’s why, within the context of all of the clinical trials that we do, we always try to collect patient samples, sometimes through the use of biopsies. This this helps us understand what’s going on with one patient’s tumor that’s different from another patient’s tumor, and help us identify the patients for the future studies and actually future approved drugs that would allow for these patients to benefit. So with that, I think I’m going to stop with this introduction and I will take any questions.
Arthur Brodsky: Thank you very much, Dr. Zamarin, for that great overview of all the different immunotherapy strategies that are being evaluated for ovarian cancer. So first, Maryann, one of our attendees asks, “Are there clinical trials for ovarian cancer as well as what is the outlook for immunotherapy and ovarian cancer?”
Dr. Dmitriy Zamarin: Sure. Absolutely. So there are quite a few trials that are ongoing in ovarian cancer. As you can imagine, the drugs that have been approved for some other cancer types, such as a class of drugs known as immune checkpoint inhibitors, these are again antibodies that would infuse into the patients that, you know, teach their endogenous T-cells to recognize and kill cancers. These drugs by themselves, unfortunately, have not been as effective in ovarian cancer as in some other cancer types, but what the current clinical trials are doing are trying to combine these antibodies with other drugs that were known to be effective in ovarian cancer, and some of these drugs are very standard, such as PARP inhibitors or chemotherapies. These trials are currently ongoing and there are quite a few of them, and these trials and one can enroll on these trials in any disease setting that a patient with ovarian cancer may have, including with the newly diagnosed ovarian cancers.
Arthur Brodsky: Thank you for that, and so now following up on that, Elizabeth from our audience asks, she also mentioned that, I believe she’s referring to herself, that she has recurrent ovarian cancer with a BRCA one mutation, and she wanted to know what is the best way for a patient to learn about clinical trial options as well as are they only off our clinical trials for ovarian cancer only offered at comprehensive cancer centers? Or can patients be treated closer to home?
Dr. Dmitriy Zamarin: So we, you know, we usually prefer for patients actually to be treated closer to home because comprehensive cancer centers tend to be located at, you know, a lot of times, the cities that may be too far for the patients to travel on, and it’s too expensive for many of these trials. Patients actually almost require to move to be in the proximity of these comprehensive cancer centers. Many trials on multi-institutional and they run throughout the centers throughout the country. There are ways to identify where the trials may be. As clinicians, we use the website now called clinical trial that clinicaltrials.gov that lists basically all of the clinical trials that may be ongoing in the world, and one may actually try to find out where the trials are by looking at the specific region of where they live. That website is not very easy to navigate because I think it’s primarily designed for them, for the clinicians as opposed to the patients. So there are other resources that may be available for the patients, including the CRI website that lists some of the ongoing clinical trials or the types of immunotherapies. In addition, there are there are support groups and specific organizations that are focusing on ovarian cancer, such as OCRA or Ovarian Cancer Research Alliance, that may have other resources for patients as well.
Arthur Brodsky: Thank you for sharing that great information, and I would also just add that, you know, you mentioned the ClinicalTrials.gov isn’t necessarily the easiest for someone to navigate, and even through our clinical trial finder, some of the information could be overwhelming, so I would also add that we have navigators who are also free that can help walk people through that to kind of help better understand the results and their options. So next on that same topic, we have a question about someone who has stage four ovarian cancer and just received chemotherapy. I believe they finished taking it, and they are curious of whether they would be able to also take immunotherapy in combination with that moving forward.
Dr. Dmitriy Zamarin: So it depends all on where the patient is in treatment. I mean, currently there are no immunotherapies approved for ovarian cancer specifically in any settings, so any type of a trial would have to be any type of immunotherapy would have to be on the trial. So some institutions may offer trials of a vaccine study, and if somebody, for example, has just completed chemotherapy and they are in remission, there are types of maintenance drugs that the patients may take. Of course, these maintenance drugs are approved. They’re not immunotherapies, they’re drugs like bevacizumab or Avastin or PARP inhibitors, but for immunotherapies, we currently don’t have any approval. So using a maintenance type of drug as an immunotherapy such as, for example, a vaccine can hopefully help a patient to prevent their recurrence, but these vaccine studies are unfortunately not very common, so one would need to go through one of these navigators or websites, as we have highlighted before, to see if there are any trials that that may be available.
Arthur Brodsky: That make sense. So at the same time, I know you mentioned earlier that at least with respect to checkpoint immunotherapy, ovarian cancer is one of the forms of cancer that it hasn’t been that effective against at the moment, so is it necessary for a patient to undergo chemotherapy first or at least try that option first before they move on to immunotherapy?
Dr. Dmitriy Zamarin: I think that chemotherapy in ovarian cancer is the most effective tool that we have, at least in the upfront treatment that the response to chemotherapy the most commonly used chemotherapy, is a combination of carboplatin with paclitaxel. It generates responses in 75 to 80% of patients. No immunotherapy has come even close so far in ovarian cancer. So in the absence of better data to suggest otherwise, we would always recommend chemotherapy. Now, can one add immunotherapy on top of chemotherapy? That’s a different question, and that’s what’s a number of trials are currently testing. They’re taking the standard of care chemotherapy and adding on other drugs, immune checkpoint inhibitors being one of them. But there could be some others as well. The goal, of course, for us is to increase the number of patients that are cured over the past 20 something years, we have made great strides in treating ovarian cancer, and the patient is living much longer, but the percent of patients that we are curing unfortunately has not changed. Over 80% of patients still have their cancer come back, and we think that it’s really in this up-front setting if we add new drugs to perhaps not just use chemotherapy, but add the immune system component to it, we can help to completely eradicate these cancers. That’s why we always encourage, first of all, development of clinical trials in this upfront setting for ovarian cancer patients, but also encourage participation of patients in the clinical trials earlier on as opposed to waiting until the cancer comes back.
Arthur Brodsky: Well, that’s a great point. You know, it’s important to note that there are still a lot of unanswered questions and that we have a lot of these promising options, scientists and doctors such as yourself are still trying to figure out the best way to utilize them, especially for individual patients. Now that we know that not every cancer is the same, even within the same type, the same form of cancer, and so regarding another one of the promising types of immunotherapies, it seems that your discussion of vaccines during your slides caught some of our attendee’s attention. Specifically, Vanessa asks, “Are there any neoantigen vaccines available for ovarian cancer right now, and then more generally, would you mind just discussing some of the cancer vaccines in clinical trials right now for ovarian cancer?”
Dr. Dmitriy Zamarin: Sure, absolutely. So I’ll briefly discuss what are the different types of vaccines there are, right? So, most commonly utilized, the traditionally used vaccine in ovarian cancer has not has been a vaccine that targets common proteins that may be expressed by ovarian cancers, but not expressed by other by other cells in the body. So, you may have heard about proteins like Mij or WT-1 and why you saw one. I know these are very sort of this sounds like very jumbled words, but this is what these proteins are called, and over the past, I would say 20 plus years, these were the proteins that that we have been focusing on, so patients with ovarian cancer would receive or would receive an injection with perhaps peptides, meaning like short pieces of these proteins or other forms of vaccines to try to stimulate body’s immunity, and in many cases, we can demonstrate that patients develop immune responses to these vaccines, but unfortunately, we never really saw shrinkage of tumors in patients with active disease, and that’s because we think that in a patient with an active disease, there are two immunosuppressed and the tumors resist these new T-cells that we develop vaccines. So many of us feel that the best time for the vaccine is probably in the setting where the patient has minimal disease, perhaps they completed chemotherapy and they need something for maintenance. This is what they would receive the vaccine against the cancer. The other problem is that as I have mentioned, there’s these shared types of proteins are not always that immunogenic. So the newer generations of vaccines called neoantigen vaccines. Those are patient-specific. They are personalized. This is dependent on sequencing your genome or the tumor genome, finding out what the mutations are and then designing the vaccine to specifically target these mutations or these mistakes in the proteins that that the cancer cell has made. They are not that many of those in ovarian cancer, unfortunately, such as in melanoma and lung cancer, there are many mutations and more opportunities to make these neoantigen vaccines. Ovarian cancers don’t have so many mutations, so we’re still working on devising best ways to generate vaccines against ovarian cancer. That would be immunogenic, meaning that they could teach the T-cells to recognize them, but this is still a work in progress.
Arthur Brodsky: I think that’s very important to note, as you mentioned immunogenic, which to our audience just means that it has already that knocked out any sort of treatment. Intervention has already stimulated the immune system and caught its attention, and it’s against these tumors that immunotherapy works best, and so one of our attendees asked kind of to that point that she heard that ovarian cancer is considered a cold tumor, which would mean a non-urgent immunogenic tumor, and that the immune system it hasn’t caught the immune system’s attention yet, and so I guess one question is, is ovarian cancer considered a cold tumor? Then another of our attendees, Jacqueline, brought up the oncolytic virus trial that you were running in collaboration with the Cancer Research Institute. So first, could you talk about ovarian cancers being potentially cold tumors, as well as the success that you’re having with your oncolytic virus trial?
Dr. Dmitriy Zamarin: Absolutely. You’re right that many of us consider ovarian cancers to be largely cold. Not all of them are cold, but many of them are cold. What do I mean by cold? That means that if we take a piece of ovarian cancer, look at it under the microscope. We don’t really see immune cells in it, meaning the ovarian cancer is not well recognized by the T cells, or it actively excludes T cells from the from the tumors so they cannot access it, and this is one of the reasons, perhaps, that these cancers are not as responsive to the common immunotherapy, such as immune checkpoint inhibitors. What many clinical trials right now trying to do is to heat those tumors up, meaning to give patients other drugs in combination with these immune checkpoint inhibitors to try to stimulate the T cells to enter the tumors. One of the strategies that was brought up is this oncolytic virus trial that we are running with CRI, and that’s in that specific trial. We would take patients with advanced ovarian cancer and we infuse an oncolytic virus. This is a virus that that has a predilection to infect only cancer cells while sparing normal cells. As you can imagine, viruses induce inflammation. So as the viruses enter the tumors and start replicating, they stimulate this sort of inflammatory or immune response, and that helps for the T cells to get into the niches and teach other T cells how to better record. The trial is still ongoing, so I can’t really speak to the efficacy of we know from this trial actually, and from some of the other studies that we have done is that this strategy can be effective in in in getting the T cells into the tumors. The time will show whether this specific virus is effective for ovarian cancer, even if the if the virus turns out to be not effective. There are many other better viruses that are now upcoming that we think could be even better. So the field is still wide open.
Arthur Brodsky: Gotcha. With respect to ovarian cancer is usually being cold and not having that immune infiltration or responses against yet are there is there anything that a patient can do with respect to their diet or other behavior to increase, I guess, their chances of their immune system recognizing it?
Dr. Dmitriy Zamarin: Well, I wish I had a good answer for this. It’s this is the question I get every day from the patients. We don’t have anything that’s proven, unfortunately, to at least from the dietary types of interventions to stimulate an immune response. We know that staying physically active is good, that the physical activity stimulates body’s innate immune system is just basically just your inherent ability to recognize infections and cancer cells. We know that patients that stay physically active tend to tend to live longer, and there may be even evidence that that may delay time to the cancer recurrence, which we think has to do a lot with the immune response, but in terms of dietary interventions, unfortunately, nothing has been proven to date.
Arthur Brodsky: I understand that definitely an exciting area, but you know, the body’s so complex it can be hard to tease out those factors, but definitely an interesting area of exploration. So now going back, you know, most of these clinical trials and immunotherapy efforts we’ve been discussing are mostly targeted at advanced ovarian cancer. Earlier, you mentioned that the neoantigen vaccines usually work better against early stage ovarian cancer. I was wondering if you could talk about any other treatment advances recently that that apply in the setting of early stage ovarian cancer.
Dr. Dmitriy Zamarin: Sure. So I don’t think that there are necessarily advances in the early stage ovarian cancer, but I think there are some advances that against ovarian cancer in general. I think I have I have mentioned bispecific antibodies in my early slide presentation and these strategies. They do have some evidence of activity in ovarian cancer, at least in the trials that have been reported. So, so and these bispecific antibodies or just tumor targeted antibodies can come in in different flavors. Some of them just is just an antibody linked to a chemotherapy drug. So the antibody that recognizes something on the surface of a tumor can bring that chemotherapy to the to the cancer and without exposing the patient to the systemic effects of chemotherapy. An example of that is immunotherapies targeting folate receptor alpha. It’s a protein that’s commonly expressed in ovarian cancers, so that’s one of them. Another type of antibody can recognize a protein on the surface of ovarian cancer cell and then, as I mentioned before, act as an anchor to the T cell to help the T cell get into the tumor, and there are such strategies, such as targeting a protein called MUHC 16. It’s also known as K one twenty-five, that’s expressed on the surface of ovarian cancer cells, and there are some drugs that are currently being explored in the clinical trials against this. I think this sort of tumor-targeted types of approaches is really the new frontier in immunotherapy for ovarian cancer, and I’m really looking forward to seeing these develop in the clinical trials and hopefully being approved for these patients.
Arthur Brodsky: I agree. Hopefully, we’ll get some positive results, then can build on those moving forward. So Brittany, from our audience pointed out a very interesting area of exploration that’s new that I think you’ll be able to shed some light on. “How do genetic mutations impact the effectiveness of immunotherapy, and how would a patient go about getting genomic sequencing? Do you have any recommendations as far as where they should go or who they should ask?”
Dr. Dmitriy Zamarin: Sure. Well, the genomic sequencing for the patient’s tumors is now is now a standard of care. The reason, at least in ovarian cancer, the reason for that is because the sequencing can help us select patients for a drug that’s known to work in some patients or not others, for example, a PARP inhibitor. PARP inhibitors work best in patients that have mutations in BRCA1 or BRCA2, or in patients that have certain patterns of mutations that leads to DNA damage known as homologous recombination deficiency. So we do
have drugs approved for patients that have homologous recombination deficiency, or HRT, namely PARP inhibitors. Because of that, any clinician that’s treating a patient can order a genomic test for patients. There are a number of them now that the commercial entities that can sequence the patient’s tumors, they usually focus on up to five hundred or sometimes even more genes that are known to cause cancer, and these can help us. Can help potentially identify the drug for the patient that may be FDA approved or the drug that’s not approved. But there is a specific clinical trial that’s ongoing targeting that mutation. These kinds of mutations, unfortunately, are not very common in ovarian cancer, as I mentioned before. Ovarian cancers are not really driven by mutations. They’re driven by very complex rearrangements in the tumor DNA, for which we unfortunately still don’t have very good drugs. We also don’t have a good way to predict from the genetic test of which patient is more or less likely to respond to immunotherapy, with the exception of a few patients that may have what we call high tumor mutational burden, meaning that they have many mutations in DNA or the patients that have what we call microsatellite unstable or MSI high tumors, and these actually can benefit from immunotherapies like immune checkpoint inhibitors, and in fact, immune checkpoint inhibitors are approved for patients with high mutational burden and or in sky high, irrespective of the cancer type, so it could be ovarian, endometrial, cervical or any other cancer. There is an FDA approved drug for those.
Arthur Brodsky: Real quick, just following up on the microsatellite instability in the high tumor mutational burden, how does Lynch Syndrome relate to that, both in terms of a patient’s likelihood of developing ovarian cancer, as well as their potential treatment options, especially with immunotherapy?
Dr. Dmitriy Zamarin: Sure. So Lynch syndrome is precisely the syndrome that leads to microsatellite unstable cancers. Lynch syndrome is a syndrome of patients have defects in order to repair DNA, and because of that, the DNA accumulates many mutations since you have many mutations. There is much more for the immune system to recognize, and these cancers tend to be much more sensitive to immunotherapy with immune checkpoint inhibitors. Patients with Lynch syndrome have a higher risk of development and DIMITRIUS cancer and colorectal cancer, as well as some other cancer types. They have a slightly higher risk of development of ovarian cancer, but the risk is not that much higher than the general population, but for the patients that do have, as I mentioned, that unfortunately they do develop these cancers. Most tend to be earlier stage, so hopefully they can be cured with just a surgery or sometimes surgery and the radiation. But for the patients for whom the cancer does comes back, we have these immunotherapy options that are approved that are available.
Arthur Brodsky: So our audience continues to show interest in the vaccines you brought up earlier. So we have two different questions that I’ll try to combine and have you answer together. So first, “Is there still hope for vaccines in late stage ovarian cancer?” and then a second attendee, June mentions that they were diagnosed with stage four ovarian cancer and, “I’ve had one recurrence but are fortunately have no evidence of disease now. So while they are in remission, would they be a candidate for a vaccine then to hopefully prevent a recurrence?”
Dr. Dmitriy Zamarin: So I’ll answer the second question first. I think like if there is a vaccine trial that’s out there and the vaccine trial seems reasonable, I would highly encourage the patients to consider those vaccines tend to have very few side effects, and again, would you have some evidence to suggest that some vaccines perhaps can prolong the time to recurrence or even prevent the recurrence from happening in the first place? The second question is that is there a hope for vaccines in ovarian cancer? Absolutely. I think that I think that there are perhaps less likely to work as single agents, however, in combination with other therapies, whether this is chemotherapy or perhaps other therapies where if you can imagine you can stimulate a new immune response against the cancer and then keep that immune response going by stimulating these T cells or further modifying the tumor so it’s more susceptible to these T cells getting in. This is the type of strategy where the vaccines are more likely to work. We have seen this work in animal models over and over and over again. Yes, we have not been able to translate this to patients as well. Up until now, but there is hope for it in the future. So I think I would stay positive about the future for the cancer vaccines.
Arthur Brodsky: That’s great to hear, and I think that speaks to a larger, a larger focus of the field and that for most cancers and most patients, it’s not going to be one single treatment that cures them. You know, we’re learning cancer’s cancer is a very complex disease and figures out all these tricks to outsmart our treatments and the immune system. So for most people, it will take a multipronged attack, which is what a lot of our clinical trials are exploring, fortunately. So now before we wrap up, I was hoping that you could just discuss just share with the audience. “How has it changed your outlook on cancer care? And do you think that immunotherapy will one day become broadly available as a first line treatment?”
Dr. Dmitriy Zamarin: I certainly hope so, and actually, I just hope so. I think I think that it will happen again. As I as I mentioned, immunotherapy perhaps has not made as much impact on the overall ovarian cancer care. I have had a few fortunate patients that have had great response to drugs like immune checkpoint inhibitors and have even been cured. These are very few patients, but the fact that we are able to achieve that with these few patients who actually had recurrent metastatic disease and no treatment options left, and I’m not going to say that this is going to be true for every patient because but by the fact that we’re able to achieve it with some patients and collect their tissue and try to understand what made them more susceptible to immunotherapy than others. That gives me hope that we can learn from these patients and that can teach us to take these approaches, combine them with something else and see how we can modify the patient who otherwise would not respond to become responsive to the immunotherapies. We’re starting to see some results in advanced patients now the results that perhaps we were not seeing just a few years back, but this is unfortunately how the trials are usually done. We start with advanced patients and then they move them to the to the upfront setting and across many cancer types. We typically see better responses in the upfront setting than in the advanced setting. Because the patients are the immune systems. I’m not yet quite beat up by radiation and chemotherapy, and what I’m hopeful for is that by including these new approaches, perhaps in the biomarker targeted fashion, meaning that we can identify a patient that is more likely to benefit from this immunotherapy as opposed to another. We can include them with the upfront therapies and then increase the number of patients that never see the cancer come back.
Arthur Brodsky: It’s very promising to hear your outlook, and, you know, with all the progress that’s been made in the past few years, it really seems like we are on the right track. So thank you, doctors, man, for sharing your expertise with us today and for our audience who ask such great questions. Unfortunately, we weren’t able to get to all of them. Many of them that weren’t answered from the audience today will be answered on our blog by doctors, a man afterwards. So stay tuned, and also, we would love to hear about you in the poll about your biggest takeaway from this conversation, in order to help us guide our future educational programs for patients and caregivers, so please take a moment to let us know and the poll to the right-hand side of your screen. Thank you again very much, Dr. Zamarin, and best of luck with your work.
Dr. Dmitriy Zamarin: Absolutely. Thank you so much.