Advancing Ovarian Cancer Treatment through Adoptive Immunotherapy

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and Co-Director of the Cleveland Clinic Sarcoma program. Today, I'm very happy to be joined by Dr. Peter Rose, a Gynecologic Oncologist here at Cleveland Clinic. He's here today to talk to us about a clinical trial of adoptive immunotherapy for patients with ovarian cancer, for which he is the principal investigator.

So, welcome.

Peter Rose, MD: Great. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. So we're going to end up talking about some new novel therapies, clinical trials related to ovarian cancer, but let's start basic. Ovarian cancer. Why has ovarian cancer been hard to treat in the past?

Peter Rose, MD: Well, there's a number of reasons. First of all, we don't really have the screening tests, so we can't really identify, and patients only present with symptoms of advanced disease. So since we don't have a screening test and patients only present with symptoms of advanced disease, by the time the patient presents, they already have advanced disease, so they're mostly dealing...

70% to 80% of our patients have Stage Three and Four disease. And while they may respond well to therapy initially, a large percentage of those patients, about 80%, will have recurrent disease, and eventually they can go through a series of chemotherapy lines, but eventually they become resistant to that chemotherapy and then options become very minimal. And so we're always looking for new treatment options.

Now, one of the big things that's happened in cancer therapies in the last five to seven years is immunotherapy, which has really started to change certain cancers tremendously. But unfortunately, for ovarian cancer, the most common type of ovarian cancer, the high-grade serous histologic type, which makes up about 70% of ovarian cancers but about 95% of the patients who have recurrent platinum resistant ovarian cancer are high-grade serous histology, we haven't done very well with immunotherapy. And that may be because these tumors don't have the mismatch repair deficiency that we see with endometrial cancer that responds very well to immunotherapy. And response rates, even when we look for markers like PD-L1 and PD-1 expression, we see this in a small percentage of patients and the response rates to these standard immune checkpoint inhibitors are on the order of about 6% to 7% with the responses being relatively short.

So one of the suggestions people have had is maybe the problem with ovarian cancer in someone who's had multiple lines of chemotherapy is that their immune system is basically exhausted. And so instead of trying to rely on their existing immune system to fight the cancer, maybe they need assistance. And so the idea of using cell therapy like harvesting cells from patients, multiplying those cells, and re-infusing them, this is the concept that we're testing in this study.

Dale Shepard, MD, PhD: And so we'll talk a little bit about the trial itself that is going on here. But I guess really quickly, you mentioned patients getting chemotherapy. I guess other things we use from a systemic therapy might be targeted therapies or genomic therapies. Do those have much of a role in ovarian cancer? Do we have the right targets, or not really, no?

Peter Rose, MD: Well, for certain tumors, for the BRCA mutated patients, we use the PARP inhibitors. And for other patients with advanced disease, we often use the anti-VEGF therapies, bevacizumab. Eventually resistance to these agents develops, and then we need to come up with an alternative.

Dale Shepard, MD, PhD: So let's go ahead and jump in about the trial. So this is a trial looking at-

Peter Rose, MD: So this is a phase two trial, which means that everybody who enters the trial gets therapy. And there actually is a randomization between therapy with the T cells themselves or therapy with the T-cells plus an immune checkpoint inhibitor, Opdivo, that you hear advertised all the time On television.

There are certain eligibility criteria, specifically because these engineered T-cells target a certain receptor in ovarian cancer called the MAG-4 receptor. It was seen in about 40% of patients with ovarian cancer, so not everybody who fails therapy would be a candidate. The patients have had to have no more than four lines of therapy, and there's a maximum age of 75 years of age. So that's for safety reasons. And the patient also has to have a certain HLA type, because this is the way these T-cells are engineered. So the two requirements are an HLA type of O2, and the tumor expressing the MAG-4 receptor.

Dale Shepard, MD, PhD: When we think about those as being criteria, is that the majority of patients that were looking for therapies or a minority?

Peter Rose, MD: No, it is probably about 35%, because the HLA typing is the most common HLA type that they're studying. 40% to 50% of those are going to be MAG-4 positive. So probably about a third of the patients should be eligible.

Dale Shepard, MD, PhD: Pretty good group.

Peter Rose, MD: Yeah.

Dale Shepard, MD, PhD: Okay, excellent. And then if we think about just general characteristics, is there anything else that differentiates you in the line of therapy? For the most part, anyone else might qualify?

Peter Rose, MD: Pretty much anybody else would qualify, yeah.

Dale Shepard, MD, PhD: Okay. And then this is with the T-cells, to double-back on that, are these T-cells that are being generated that are patient-specific or the-

Peter Rose, MD: Patient-specific. So they're harvested T-cells that are then engineered and directed against the MAG-4.

Dale Shepard, MD, PhD: All right. What does treatment look like with these kinds of therapies?

Peter Rose, MD:

So it's complicated. It's a long process, and we are being helped tremendously by the bone and marrow transplant team at the Cleveland Clinic. Dr. Sauter is the lead division director, and he's been helping tremendously.

But basically, there's the pre-screening with the MAG-4 and the HLA typing, and then there's, once someone's entered on the study leukapheresis, and then these cells go to T-cell manufacturing, and then the patients get randomized between T-cells alone or T-cells plus nivolumab. Then there's admission to the hospital for lymphodepletion, because we have to... It turns out that these new cells will respond best in a lymphodepleted person. And then there's the T-cell infusions and a series of post-infusion visits.

So this is really a big undertaking. All these T-cell therapies are very involved, but really an exciting prospect for us to have this in ovarian cancer. We've had a T-cell TILT study in cervical cancer for about five years, and we have some five-year survivors, which is really amazing when you talk about the average survival for cervical cancers on the order of about 24 months with all the new drugs we have.

Dale Shepard, MD, PhD: Is that success in cervical cancer T-cells alone or T-cells in combination with immunotherapy-

Peter Rose, MD: It's a T-cell alone study.

Dale Shepard, MD, PhD: ... or checkpoint inhibitors?

Peter Rose, MD: It's a T-cell alone study.

Dale Shepard, MD, PhD: On this particular trial, are patients allowed to cross over? So if they're in a T-cell lung group and they have disease progress, can they cross over and start taking the immunotherapy as well?

Peter Rose, MD: I don't think so. It's randomized between these two designs, one T-cell plus checkpoint inhibitor.

Dale Shepard, MD, PhD: And of course, typically if people are getting chemo, they're coming in every three weeks, for instance, to get these treatments. This is a long course to get to treatment. It's very involved to get the treatment. But are there continuous treatments or is this a one-time treatment and-

Peter Rose, MD: A one-time treatment, except for the patients who receive the checkpoint inhibitor.

Dale Shepard, MD, PhD: And they'll get the usual.

Peter Rose, MD: They'll continue to receive that every four weeks.

Dale Shepard, MD, PhD: What is this particular study looking for in terms of endpoints? Are they looking for progression-free survival, or response or survival?

Peter Rose, MD: Well, you have to have measurable disease. So response progression for your overall survival. Those standard three endpoints.

We're fortunate that here at the Cleveland Clinic, we have the bone marrow transplant service that can help us put this type of study through and conduct it. We've actually done fairly well. And this is an international study. There are a number of US sites. One in Sioux Falls has treated one person and one in Spain has treated one person. But otherwise, we've treated four patients and are about to treat the fifth patient.

Dale Shepard, MD, PhD: Wow.

Peter Rose, MD: So we're very excited about it because it gives us an option that we don't otherwise have. One of the things about clinical trials, I think, that's important for people to realize is that we have a lot of active drugs in ovarian cancer. We have eight active drugs, but when you have a clinical trial, now you have nine options. And if you have two clinical trials, now you have 10 options.

So we have other clinical trials looking at other things that are very novel too, like oncolytic viruses, and there's a tremendous expansion in antibody drug conjugates that are ongoing, and we've had some recent drugs approved in that setting. Mirvetuximab and HER2 or trastuzumab deruxtecan, so we've got approvals recently for those drugs. But it's an exciting area, especially cell therapies. I think our cell therapies are starting to take off more. They've done a great job in lymphoma leukemia, but just getting into the touching their feet into solid tumors.

Dale Shepard, MD, PhD: And I guess the specificity of these targets helps because that's one of the problems in solid tumor. It's being able to find a reproducible target in all the cells.

Peter Rose, MD: Right. That's a good point.

Dale Shepard, MD, PhD: So, we'll touch upon some of these other things that are exciting, but doubling back to this study really quickly, I guess a couple things come to mind. One is the importance of, I guess, team science and team work in clinical trials, for lack of a better way to put it. One of the things we do really well here at the clinic is work together as a group. So how did that work?

So a lot of places, gynoc is in one group and BMT is another group, and everyone's got their own little silos, but you're working with the bone marrow transplant and the cell therapy group, and you've successfully been able to open this trial and get people involved. So how did that all come together? And what are the lessons learned, I guess, if people are trying to put these groups together?

Peter Rose, MD: Well, I think everyone wants to see these new therapies come to fruition. We're fortunate that we have a lot of resources at the Cleveland clinic. Fortunately, bone marrow transplant also views this cellular therapy important and that they would make the time to participate in the trial, because we can't do this independently. We don't have this expertise, really. But I think it is one of the benefits of being in a large institution that has a lot of depth. We don't have one bone marrow transplant physician. We have 10, or however many.

Dale Shepard, MD, PhD: Absolutely.

Peter Rose, MD: So, different people are involved in the service because it rotates who's going to be involved, and everyone's been very helpful. I think it clearly speaks to the benefit of a large facility that we have here and the teamwork that's part of the attitude.

Dale Shepard, MD, PhD: I think that, I guess another thing we think about team science, if you will, would be this is being done through a cooperative group. So just gives us a little bit of background about how, really just quickly, what cooperative groups are and how the cooperative group structure helps make these kinds of trials possible.

Peter Rose, MD: Okay, so the cooperative groups were established approximately 50 years ago, at least our cooperative group, 50 years ago. And it was a gynecologic oncology group, and basically involves everyone dealing with the gynecologic cancers, be it radiation therapists, medical oncologists, and gynecologic oncologists, and all the support staff, the data monitoring people, data managing people, and the nurses.

So there's a long legacy that most people don't realize of how these groups have worked together to try to answer basic questions in oncology, or in this case, gynecologic oncology, like whether one chemotherapy regimen would be superior over another. Or, there's surgical studies. Most of the studies deal with chemotherapy, but there's some surgical studies about lymphedema following lymphadenectomy, secondary cytoreductive surgery. We have a new one ongoing with HIPEC in neoadjuvant chemotherapy and randomization to HIPEC, versus non-HIPIC at the time of interval, the bulking surgery.

So there's a lot of studies going on, but it also is important for people to realize that we don't have the answer to something, but sometimes neither does anyone else, and only through a cooperative mechanism do we have enough patients to answer a question in a critical time point. By that, I mean we could try to mount a study at the Cleveland Clinic or the Cleveland Clinic hospital system to accrue 500 patients, but by the time we do, the question that we're asking probably is no longer relevant because things have changed. So the nice thing about these cooperative groups is that they can...

We have a hundred hospitals that we work with in our cooperative group, and we can answer questions in a much more timely fashion. We can do a phase two trial in four to six months. We can do a large phase three randomized trial in three to four years. And then we have four or five years of help. So basically within a decade, we get an important answer. So if we don't put patients on clinical trials, that's okay, but then we don't answer any questions.

And the patients who come for treatment are actually being treated by the most recent clinical trial, which was completed, because it's the basis for all of our care. We obviously want to provide the best treatment. If we have a study that shows that one treatment is superior to the other, obviously we're going to use that treatment. And I think that may be hard for some patients to realize, that they may not be in a clinical trial, but they're being treated based on a clinical trial, because all medicine is based on a clinical trial.

Dale Shepard, MD, PhD: And I guess you get the added scientific rigor of having multiple locations instead of one small group generating the data.

Peter Rose, MD: Well, in general, there's a lot of bias when one group generates the data. And usually when those studies go to multi-institutional studies, the outcome is not as robust as seen in a single institution.

Dale Shepard, MD, PhD: Absolutely. So, exciting things with the T-cell therapy. You touched upon it a little bit, certainly antibody drug conjugates were a hot topic at ASCO this year. What are some of those other exciting things that are happening within gynecologic cancers right now in terms of targets or new molecules that people are excited about?

Peter Rose, MD: Well, MMR deficiency is most common in endometrial cancer. If you look at all the cancers across the board, endometrial cancer has the most frequent MMR deficiency mutation. So that opened up in the last year a world of studies that were published in New England Journal Medicine looking at pembrolizumab or dostarlimab in the setting of metastatic disease. And we have a number of ongoing trials looking at immunotherapy in addition to the standard therapies that we gave. So a patient would normally get radiation therapy, but in this case may get radiation therapy plus immunotherapy. We also in cervical cancer have seen immunotherapy also very effective, and it's become part of our standard of therapy for advanced metastatic disease.

So there's a lot of interest in expanding immunotherapy whenever we can. The problem we have, like I said, with the high-grade serous tumors, which is our biggest fatality rate, is in ovarian cancer, and the problem is that we just don't have the immune targets that we want. So we're excited about this T-cell study because a way of taking cells from your body, multiplying them, and reinfusing them in a quantity that'll be sufficient to be beneficial. But of course, we have to see. We're really in the very beginning of this. We've entered some patients and started their treatments, but we'll still have to see how they're going to respond to treatment.

But I think one of the reasons I am glad you invited me to come talk about this is that we want to make clear to patients in the community that if they failed a number of lines of therapy, we have some experimental treatments that are open, and some which have moved into phase three settings because the phase two trials were so positive, like the oncolytic virus studies. So I think it's always good to make a phone call to an institution, see what studies they have open and whether they'd be a candidate for it. The clinicaltrials.gov, it's a great thing for physicians, but for patients, I think it's overwhelming.

Dale Shepard, MD, PhD: Yeah, a little clunky and overwhelming.

Peter Rose, MD: Yeah, it's overwhelming. Their eligibility is hard for them to understand, and prior treatment requirements are sometimes confusing to patients. But encourage patients to call the Cancer Answer Line and see if they're candidates for trials, and we can just screen them for that.

Dale Shepard, MD, PhD: Absolutely. Well, it looks like you're on the way to answering an important question about T-cell therapies and how those might work in ovarian cancer. It looks like exciting times. Good luck with the trial. Thanks for your insights on management of gynecologic cancers. Thanks for being with us.

Peter Rose, MD: Oh, great. Thanks, Dale.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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