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Ovarian Cancer and Immunotherapy Breakout Session at the 2020 CRI Virtual Immunotherapy Patient Summit

November 23, 2020

Ovarian cancer is diagnosed in an estimated 300,000 women around the world each year. While significant advances have been made in conventional treatments, survival rates have only modestly improved. A new, breakthrough approach is required. At the 2020 CRI Immunotherapy Patient Summit, we hosted a special breakout session on ovarian cancer and immunotherapy to educate and empower patients, caregivers, and advocates.

Kunle Odunsi, M.D., Ph.D., a gynecologic oncologist specializing in cancer immunotherapy at Roswell Park Comprehensive Cancer Center, led the session, discussed new approaches, treatments, and clinical trials in gynecologic cancers, and answered questions from the audience.

Dr. Odunsi opened the session with a brief overview of immunotherapy for ovarian cancer. He emphasized that genomic sequencing and genetic testing has become standard of care for all ovarian cancer patients. He said, “The bottom line is that any patient with a gynecologic cancer should be asking their treating physician about genomic testing, sequencing, in order to understand the nature of the cancer and select the most appropriate therapy.”

Dr. Odunsi explained that although there aren’t any approved immunotherapies for ovarian cancer yet, it’s a very promising area of research which makes it crucial to ask your doctor about clinical trials that may be available to you.

Dr. Odunsi also answered questions about other gynecologic cancers, such as cervical and uterine cancer. Dr. Odunsi explained that the majority of cervical cancers are caused by the human papilloma virus (HPV). Cervical cancers therefore have higher mutational burdens (when compared to ovarian cancer), which makes it more responsive to immune checkpoint inhibitors. Uterine cancers generally also has a higher mutational burden, making them highly responsive to the same immune checkpoint inhibitors.

Toward the end of the breakout session, Dr. Odunsi reflected on how far the field of immunotherapy has come, especially over the past 10 to 15 years.

“I think the immune system is the most powerful weapon that we have in the fight against ovarian cancer. And we need to continue to study how best to use it. And I think we’re on track.”

OVARIAN CANCER AND IMMUNOTHERAPY SESSION TRANSCRIPT

Tamron Hall: Welcome back. Now it's my pleasure to welcome and introduce our doctor specializing in ovarian cancer and immunotherapy. Dr. Kunle Odunsi. Dr. Odunsi is joining us from the Roswell Park Comprehensive Cancer Center in Buffalo, New York. At Roswell Park. Dr. Odunsi is the chair of the department of gynecologic oncology as well as the executive director of the center for immunotherapy. He's also an associate director of the Cancer Research Institute Scientific Advisory Council. Thank you at Dr. Odunsi for being here with us and answering our questions about cancer immunotherapy for ovarian cancer. A cancer that affects more than 200,000 women worldwide each year.

We also have with us Brian Brewer from the Cancer Research Institute, who will be sharing your questions with Dr. Odunsi. So please be sure to put them in the Q&A box.

Dr. Kunle Odunsi: Oh, thank you very much for the introduction, Tamron. I'm very pleased to be on this program this morning, actually it's afternoon. And thanks to CRI for putting this together. It's really a wonderful opportunity to update ourselves about some of the recent advances in ovarian cancer immunotherapy.

So what I plan to do today really is to focus primarily on some of the next generation strategies for ovarian cancer immunotherapy, and I've listed three aspects. One is the use of adoptive T cell therapies. Number two is the use of neoantigen vaccines. Number three is really trying to understand who will best respond to immunotherapy in ovarian cancer.

So before I go on to the next slide let me just quickly highlight the strategies for immunotherapy in general. As many will know on this call, that there's the use of concept vaccines, the use of immune checkpoint inhibitors, and really those are the most popular type of immunotherapies. Then there's the use of another strategy which I may touch upon during this discussion, the use of oncolytic viruses. These are viruses that are unique in their ability to selectively destroy cancer cells and spare normal tissue. And then the real question is, who is going to respond? How can we identify those who are going to respond?

One of the areas that we and others have focused upon is this aspect of using the T cells. T cells are the major cells that kill cancer cells. And so our current generation approaches for using T cells involve taking the blood, taking blood from a patient, taking it to a special lab, engineering those T cells, those immune cells and generating large numbers to give back to patients. Many will be familiar with CAR T cells. That's an example of T cells used for adoptive T cell therapies.

And as we all know, they have been very successful for treating liquid tumors. Some leukemias and some lymphomas. But not so much with solid tumors, including ovarian cancers. So the current generation of T cells essentially were asking these T cells, these immune cells to arrive in the tumor and be able to do their job. And yet they face counter attack by the cancer cells. So that is really what's going on. Because the area of the tumor, you can imagine that it's like a battle ground between the T cells and the cancer cells.

So some of the new generation approaches involve putting a shield around the T cells so that they can resist counter attack against the tumor. And there are ongoing clinical trials testing these approaches at Roswell Park and in other cancer centers where in fact the T cells are stronger, they are able to persist longer and be able to survive and resist counter attack by the tumor.

So I will like to talk about personalizing immunotherapy. There are really two aspects of this. In the beginning, I talked about the neoantigen vaccine approach. Because one of the fundamental features of the immune system is to try and discriminate between self and non-self. And that's why the immune system has no trouble fighting off bacteria and viruses. So if you give a flu shot, for example, the immune system knows that the flu virus is foreign, when it sees the virus the next time it's able to go on the attack. So the question is, what discriminates a cancer cell from a normal cell? And one of the discriminating factors are actually the mutations in the cancer cells. And so one approach that is called neoantigen vaccination is to take the information, the knowledge of the mutations in the cancer and use that to construct personalized vaccines for patients.

So this has been tested in several institutions across the country now, and it allows the ability to tailor a vaccine, to personalize a vaccine towards a specific patient. The other aspect of personalizing therapy is to really understand, what is going to work best for a particular patient? And so this requires developing biomarkers. Biomarkers are tests that can predict potential responsiveness. At Roswell Park for example, we came up with what we call immune report card, which is a panel of about 300 genes that relate to the immune system that allows us, for example, to try and select the best possible immunotherapy. Because if you recall, not all immunotherapies are the same, and not all immunotherapies will work in each and every patient. So it's going to be important to select the best type of immunotherapy for each particular patient. And I'll stop there and take questions.

Brian Brewer: Thanks again, Dr. Odunsi for being here, it's always wonderful to see you. You're an associate director of our scientific advisory council and I've enjoyed working with you for so many years. So good to see you. So let's get right into these questions. I'll just remind folks who are watching. You can continue to leave your questions in the Q&A. We will try to get to as many of them as possible. If we don't get to them all today, we will follow up in a blog post after today's event.

So, first question, Dr. Odunsi, does an ovarian cancer patient have to undergo chemotherapy before receiving immunotherapy?

Dr. Kunle Odunsi: So chemotherapy as we all know is the standard of care. So the standard of care for ovarian cancer is surgery followed by chemotherapy and more recently followed by some forms of maintenance therapies. It is not required to get chemo before immunotherapy because in fact, in some settings, chemotherapy might help the ability of immunotherapy to work better. So it is not required. In fact, several studies over the last couple of years have combined chemotherapy with immunotherapy. Some of them with modest benefit. Those results have not been significantly positive, but there are patients who benefit from those combinations.

Brian Brewer: For a lot of patients who are learning about immunotherapy for the first time, or have heard all the stories about chemotherapy for as long as that's been around, it might sound counterintuitive that giving chemotherapy could help the immunotherapy work more. So, can you tell us a little bit about how that happens.

Dr. Kunle Odunsi: So some chemotherapies are able to kill cancer cells in a particular way. And it turns out that the way in which a cancer cell dies can have implications for the immune system. There is a form of cancer cell death that can actually activate the immune system and thereby increase the potential benefit of immunotherapy. So that's how the two can work. And so that's a great question. For years we've thought chemotherapy is immune suppressive, but in fact depending on how you use it, chemotherapy can help immunotherapy.

Brian Brewer: That's fascinating. And learning about combination therapies and how things can synergize and have better effect on patient, it's just great fascinating stuff. Next question from an audience member about cancer vaccines. What cancer vaccines are available for ovarian cancer being studied in ovarian cancer?

Dr. Kunle Odunsi: So, there are two broad categories of cancer vaccines that are available. The first category are cancer vaccines against what we call shared antigens. These are proteins that are expressed on cancer cells that potentially are not expressed by other normal tissue. And there are very few of those. In fact, if you dig deep, there are only a very small number. And one of the key ones, is a protein discovered at the Ludwig Institute for Cancer Research called NY-ESO-1. NY because it was discovered in New York City initially in a patient with cancer of the esophagus.

So we and others have tested this vaccine across a broad category of patients. And although we see some signal of efficacy that it works, we're able to induce immune responses. And in fact, some patients have prolonged remission. It's not sufficient. So cancer vaccines need to be combined with other strategies.

The second major type of cancer vaccine is the use of this neo-antigen vaccines that I talked about that relies on the mutation in the cancer in order to create the vaccine. So those are the two broad categories where you are either targeting a shared antigen or you're targeting a neo-antigen.

Brian Brewer: I'm going to skip ahead since you bring up again the sequencing and identification of either personalized or shared antigens here. And it gets back to the immune report card that you spoke about that you have at Roswell Park. How does a patient know to ask, or must a patient be proactive in asking for this type of, it's called sequencing, genomic sequencing, and who does a patient ask for that? Or is it just standard? Is it just going to happen?

Dr. Kunle Odunsi: Those genomic sequencing testing at the present time are not standard. So I think it's important for a patient to ask. But many cancer centers around the country, it's almost automatic. Many cancer centers have molecular testing program or personalized medicine programs and so it may be standard in many cancer centers. But I think it's important for the patient to be proactive and ask your doctor about getting some of these testing.

Brian Brewer: Are those tests part of a clinical trial? Are they part of a patient standard treatment?

Dr. Kunle Odunsi: So those tests have actually now become part of standard treatment. So for example, in ovarian cancer, it's very important for us to know whether a patient has a BRCA mutation or not because that has tremendous implications for all kinds of treatment plan that we make. And BRCA mutation can also, BRCA type mutations can also help us in planning treatment. So it's automatic for us now in ovarian cancer patients in many institutions to get this genomic testing.

Brian Brewer: Speaking of mutations, let's talk about Lynch syndrome for a moment. We heard yesterday from one of our patient panelists, Stephen Estrada, who had colorectal cancer, having Lynch syndrome made him more likely to respond to checkpoint blockade immunotherapy. And of course he fortunately had a complete response. Is the same situation, or does Lynch play a role in ovarian cancer patients? And do you see any, if so, any similar responses?

Dr. Kunle Odunsi: We actually do not see a lot of Lynch syndrome patients developing ovarian cancer. They are more likely to develop uterine cancer, endometrial cancer. And in endometrial cancers, when they have Lynch syndrome, they have what we call microsatellite unstable tumors. Those are very responsive to immunotherapies. In fact, there has been a lot of FDA approvals for the use of immunotherapy for patients with Lynch syndrome or microsatellite unstable tumors across many cancer types. In the few ovarian cancer patients where we see MSI-high, microsatellite unstable tumors, those patients may also benefit from immunotherapy. But there are very few numbers.

Brian Brewer: What about patients with autoimmune diseases? What special considerations go into play for them?

Dr. Kunle Odunsi: In patients with autoimmune diseases, the use of immunotherapy has to be considered very carefully. Traditionally in many clinical trials, those patients have been excluded in clinical trials because of the potential for many immunotherapies to cause auto-immune side effects. It can affect the thyroid gland, the pancreas, the adrenal gland, almost any organ system in the body. Can have side effects from immunotherapy. So if you already have pre-existing autoimmune disease, it's going to be important to consider the severity of the autoimmune disease, which organ is it affecting, and work with your doctor to see whether or not you might still be able to receive immunotherapy.

In many instances for us, if the autoimmune disease is well controlled, we work with the patient to try and see whether we can try to still use immunotherapy paying very careful attention to the potential for this side effects.

Brian Brewer: Let's talk about PARP inhibitors and combination with immunotherapy. Are those taken sequentially together? Can patients be on those indefinitely?

Dr. Kunle Odunsi: PARP inhibitors have actually made a major impact in ovarian cancer therapy over the last few years. In fact, new guidelines, patients who... All ovarian cancer patients essentially can go on maintenance therapies with PARP inhibitors. Or the patients who are most likely to benefit are patients with BRCA mutations or patients with what we call HRD, homologous, recombination deficiency. BRCA type phenotype. Those patients benefit from PARP inhibitors. And it appears as if they also benefit more from immunotherapy. So it makes sense to combine. And when we combine, we tend to use them concomitantly.

Some of the results indicate that the response rates are better for patients receiving the combination, but there's still a large majority of patients who are not responding. And one of the major areas of research is to understand, what are the additional factors that will predict who's going to respond and who's not going to respond?

Brian Brewer: And what are some of those factors? Again, this is complicated to all squeeze into the short amount of time we have, but if I'm a patient and I'm considering entering a clinical trial, for instance, what might be some of those factors? I think we're still getting that question. So if we could just go over that again briefly.

Dr. Kunle Odunsi: So some of those factors into the intrinsic... so the property of the tumor itself. So ovarian cancers are cancers without a high mutation burden. So they tend to be not responsive to immunotherapies in general. So if you look at clinical trials of single agent immune checkpoint inhibitors in ovarian cancers, the results have not been very impressive. We see response rates in the range of maybe 5% to 15%. So it's going to be important to combine with something. And that is really going to require overcoming some of the mechanisms of resistance. There are so many of them. There are immune cells, for example, within the tumor that actively suppress the T cells. The T cells are the most critical.

So you have other immune cell populations that are frequently present in ovarian cancers that can suppress the T cells. And then you have ovarian cancer making some additional like chemicals that can suppress the T cells. So I think the more we understand these aspects of ovarian cancer, the more we can better target.

So for example, one recent study from our institution shows that the ascites, okay, the fluid that is produced by ovarian cancer itself is highly immunosuppressive. So you can imagine if you give the immune checkpoint inhibitor immunotherapy in a patient who has ascites, the fluid sitting in the abdomen. When the T cells get to the tumor, you can imagine that it's going to suppress the T cells.

Brian Brewer: What about other types of gynecologic cancers? Do you see the same thing in cervical cancer or endometrial cancers, uterine cancer?

Dr. Kunle Odunsi: Cervical cancer is a little bit different because we know what causes the majority of cancer of the cervix, human papilloma virus. So because of that, cervical cancers actually have higher mutation burden compared with ovarian cancer, for example, and it's been more responsive to immune checkpoint inhibitors. Uterine cancers, a significant proportion have this MSI-H (high microsatellite instability), which is part of the Lynch syndrome. Therefore, they respond to immune checkpoint inhibitors. In fact, in uterine cancers, there's a group that has what we call ultra-mutated. They have tons of mutations. And they are very highly responsive to immune checkpoint inhibitors.

So the bottom line is that any patient with gynecologic cancer should be asking their treating physician about some of these genomic testing, sequencing testing in order to understand the nature of the cancer and select the most appropriate therapy.

Brian Brewer: Let's talk about TMB again, tumor mutation burden. What causes that and what does that imply for a patient who's considering treatment with immunotherapy?

Dr. Kunle Odunsi: So the tumor mutation burden is simply asking, what are the genetic alterations in the tumor? What is the frequency? And the more the mutations, the more the cancer cell is going to be different from normal cells and therefore the more the immune system is going to likely recognize them as foreign. So you can imagine if you now use an immune checkpoint inhibitors, you can generate immune cells, T cells against this foreign cancer cells. In ovarian cancer there's not a lot of mutations. The major driver mutation is a gene called P53. Other than that, you see very few mutations. What you see in ovarian cancer is what we call copy number variation. Where the chromosomes are very abnormal, but you don't actually see a lot of mutations.

Therefore, it's not that immune checkpoint inhibitors cannot work. We think they can work. A, we need to select in which patients are they going to work in. And secondly we need to find other approaches to change the environment of the ovarian cancer so that there are more T cells so that it becomes more conducive to immunotherapy.

Brian Brewer: We have another question. Again I'll remind all of you watching to please leave your questions in the Q&A. We certainly won't get to all of them today, but we will be following up after today. So please do share your questions and we'll get them to Dr. Odunsi. One question we have that has come in is, age and whether or not that's a factor in a patient's response to immunotherapy. What can you say about that?

Dr. Kunle Odunsi: First of all, for the longest time we used to think that patients who are older are unlikely to respond to immunotherapy similar to how we used to think about chemotherapy and immunotherapy. It's become clear that patients, even older patients can respond very well to immunotherapy. If you recall, one of our former presidents responded very well to immunotherapy when he had metastatic melanoma. So age is not a barrier, provided someone is healthy and it's appropriate to treat that patient with immunotherapy.

Brian Brewer: That's really good to hear because I'm not getting any younger. Any advice you give to patients on how to stay healthy so that they can respond well to treatment? So diets and nutrition is something we get often asked. Anything you might say to a patient about that?

Dr. Kunle Odunsi: I think diet, nutrition and physical exercise are very critical. We did a study recently at Roswell Park where we, led by one of my colleagues, Dr. Emese Zsiros, where she looked at the physical activity of women with ovarian cancer using a Fitbit. We attached Fitbit to these patients and simply asking the question, "How many steps do you take a day?" As well as recording the heart rate and blood pressure and all of those things. What we found is that the majority of our patients actually take very few steps. Even though they consider themselves active, you might argue it's because they are sick and like, what do you expect? Therefore they are unlikely to be active. But to the extent possible, if physical activity can be increased, this may actually have significant implications for the immune system. And this has been shown in some other studies. So that is one advice.

The second advice actually relates to therapy. Making sure the patient is asking the right questions from their doctors. Asking about clinical trials. What clinical trials are available? And why select one clinical trial over the other? Are there special tests that need to be performed in order to select a clinical trial? Those kinds of questions are very critical.

Let me add one more aspect that I touched on very briefly in the beginning and that is the use of oncolytic viruses. These are viruses that are very powerful. They are engineered to selectively destroy cancer cells and spare normal tissue. The major benefit of these viruses is that they can overcome many of those mechanisms that we talked about because they can directly destroy cancer cells and then they send a danger signal all around to say there's danger here, immune system, you got to come on and fight. And when that happens, the immune system is called to action and begins to fight the cancer cells. This viruses can also be used to deliver cargo into the tumor. And we and other staff begun to engineer these viruses so that they can deliver some drugs or some approaches into the tumor environment and make it even better to respond to immunotherapies.

Brian Brewer: It's really amazing what research makes possible that we've gotten this far and that we seem to be accelerating at another faster pace. And so it's so more important than ever to keep the research going. One question we also get from some audience members is, let's say they've received one type of immunotherapy. They may or may not respond to it. Does that make them ineligible to receive another type of immunotherapy or can they consider going into another trial or receiving another treatment?

Dr. Kunle Odunsi: So the short answer is, they can receive another type of immunotherapy, but I think it's important for the treating physician to understand, what is the, again, I go back to the testing. What is the most likely immunotherapy that the patient is going to respond to? Because again, immunotherapy is not just one type. There are different types of immunotherapies. So it's going to be important to think through, what is the next best approach for that particular patient. And that may depend on some of the testing that we've talked about already. And this patients may be put on other clinical trials testing other approaches of immunotherapies. So, being on one type of immunotherapy does not preclude going on other types of immunotherapies.

Brian Brewer: One really good metaphor I heard for this is kind of the lily pad theory, where you just want to get onto that next lily pad. And you never know what's going to come down the road. There may be another treatment and in development pipeline, just waiting on the horizon. If you can just get to that next lily pad. So let's talk about the future briefly. Because as I said, it seems like we're approaching it faster than ever before. What do you see about the future of immunotherapy for ovarian cancer, uterine cancer? And do you ever think it's going to completely supplant chemotherapy or radiation therapy or will we always see combinations?

Dr. Kunle Odunsi: I think the future for ovarian cancer is going to require, again, this whole concept of generating a large number of immune cells, the T cells, and that can be done using the vaccines that we talked about, and then using checkpoint inhibitors. So we're going to have combinations going forward. And the combination again, will be combination of immunotherapies themselves. Vaccine plus checkpoints, adoptive cell therapy plus checkpoint. And then somewhere in the mix was to going to use chemotherapy but we're going to be using it at a much less, either less dose of chemotherapy, or much less frequency, or less duration of the use of chemotherapies. As immunotherapies as we continue to understand how best to put these combinations together, I think we're going to use chemotherapy less and less.

Brian Brewer: Very interesting. Any final words that you want to share with anyone who's listening today and learning about immunotherapy for the very first time?

Dr. Kunle Odunsi: Well, some of my thoughts is that I think we've come a long way from, especially over the last 15, 20 years in understanding how the immune system interacts with ovarian cancer. We now have better understanding. And even though there are no approved immunotherapies for ovarian cancer as of yet, it's only a matter of time. It's going to require some form of combination. It's important to talk to your physician about ongoing clinical trials, and also to talk to your physician about sequencing tests, next generation sequencing tests in order to better understand the nature of the cancer and what is the best immunotherapy approach. I think the immune system is the most powerful weapon that we have in the fight against ovarian cancer. And we need to continue to develop. We've made progress. We need to continue to study how best to use it. And I think we're on track.

Brian Brewer: Well, that's really wonderful to hear. I lost my grandmother to ovarian cancer about 30 years ago. So it's so nice to know that we're making so much progress and that there's more hope than ever before for patients. Once again, those watching, we're sorry if we didn't get to all of your questions today. Please continue to leave them in the Q&A, we'll follow up after today's event. Which of course, we're also recording. This entire session will be available to you to view on demand next week. So, Dr. Odunsi, thank you again so much for being here with us today. Really enlightening.

Dr. Kunle Odunsi: Thanks for having me.

Tamron Hall: Dr. Odunsi, thank you for sharing with us the latest updates on immunotherapy for ovarian cancer. We hope we answered your questions here, but if not, Dr. Odunsi will follow up on the top unanswered questions in a blog post on the Cancer Research Institute website. In the meantime, I encourage you to continue to explore the CRI resource guide. And if you haven't already, schedule your free confidential clinical trial navigator consultation. Thank you again and we'll be right back.

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