Prostate Cancer and Immunotherapy with Dr. Sumit Subudhi
Roughly 1.3 million people receive a prostate cancer diagnosis each year, and if discovered at an advanced stage, effective treatment options are limited. That’s where cancer immunotherapy offers new hope, including an FDA-approved therapeutic cancer vaccine, an FDA-approved checkpoint inhibitor, and many more promising treatments in clinical trials. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on prostate cancer and immunotherapy to educate and empower patients, caregivers, and advocates.
Sumit Subudhi, M.D., Ph.D., medical oncologist and immunologist at The University of Texas MD Anderson Cancer Center, led the session on immunotherapy for prostate cancer, discussed exciting scientific and clinical research, and responded to questions from patients and caregivers in the audience.
Dr. Subudhi reviewed ongoing clinical trials combining different types of immunotherapy with each other or combining immunotherapy with other conventional anti-cancer therapies like chemotherapy.
He also emphasized the importance of asking your health care team about genomic sequencing, noting that it is not standard of care for prostate cancer patients. Understanding the tumor mutational burden of your tumor can indicate a better response to immune checkpoint inhibitors. However, doctors will often recommend a prostate cancer patient undergo a known life-prolonging standard treatment, like hormone therapy, before enrolling in an immunotherapy clinical trial.
One attendee asked if you need to continue immunotherapy indefinitely, or if, at a certain point, you can end treatment. Dr. Subudhi explained, “We hope that our immunotherapies can be given for a finite amount of time, because your own immune system will have a memory for the cancer. And so anytime the cancer comes back, it’ll be able to fight it.”
Toward the end of the breakout session, Dr. Subudhi considered how incredible it is to succeed in curing prostate cancer patients with immunotherapy—patients who were otherwise considered uncurable. He credited his own motivation and inspiration to the groundbreaking research of his mentor, Dr. James P. Allison, who was awarded the 2018 Nobel Prize for his work developing a lifesaving immune checkpoint inhibitor.
Dr. Subudhi also acknowledged that so much of the progress made in the field of immunotherapy has relied on the participation of patients in clinical trials.
“I believe our patients are taking a risk,” he reflected. “They’re helping us innovate the future… and develop even better trials.”
PROSTATE CANCER AND IMMUNOTHERAPY SESSION TRANSCRIPT
Tamron Hall: Hello, and welcome back. It’s my pleasure now to introduce to you Dr. Sumit Subudhi from MD Anderson Cancer Center in Houston, Texas, who is here to fill us in on the latest advances in prostate cancer immunotherapy. Please be sure to leave your questions for Dr. Subudhi in the Q and A box. Brian Brewer from the Cancer Research Institute will be sharing your questions with Dr. Subudhi. So please be sure to put them in the Q and A box. Thank you, Dr. Subudhi for sharing your expertise and insights with us today.
Dr. Sumit Subudhi: Thank you Tamron for that kind introduction. So, when we think about the immune tumor microenvironment, we’d normally think of just the good cells. But what we need to be very clear about is that the immune system consists of good cells that help kill the cancer and bad cells that help the cancer grow. So, on this slide here, all the cells to the left are cells that actually the cancer uses to grow and all the cells on the right are the ones that actually kill the cancer. So, one of the goals of immunotherapies, whether they’re vaccines or immune checkpoint therapies is to actually change this balance. So, you get more of the good immune cells that help kill the cancer and less of the bad immune cells that help the cancer grow.
So, one of the issues in prostate cancer and why immunotherapies have had limited successes as opposed to in cancers like melanoma, lung or kidney, is that there are very few T cells in prostate cancer within the tumor microenvironment. So, on the left, what you’re seeing is you’re seeing a picture of prostate cancer and in brown or in purple actually I should say, are T cells. And you can see there’s very few T cells. But after you give immunotherapy, you can see that you can drive cells into the prostate cancer and that’s shown on the right.
Brian Brewer: Thanks Dr. Subudhi for that introduction of prostate cancer. I know it’s one of the most common cancers out there. There’s a lot of hope that immunotherapy will or can help patients with that disease. So, we have a lot of questions coming in and so let’s just jump right in there. So, the first one is, we’ve learned about clinical trials and knowing that these are a way to receive either experimental treatments or new combinations of treatments that haven’t been given that way before, are there any really promising trials out there right now in immunotherapy for prostate cancer?
Dr. Sumit Subudhi: Yeah, there were actually a few Brian, thanks for that question. And I think it’s the combination trials that I’m most excited about. There are trials that are combining two immunotherapies together or immune checkpoint therapies with chemotherapy or what we call, targeted therapies like tyrosine kinase inhibitors, example, being cabozantinib. So those are trials that I’m looking forward to seeing how patients respond to them.
Brian Brewer: So we’ve heard also about checkpoint blockade therapy. And we’ve seen this be very successful in other types of cancers like melanoma and certain lung cancers and various cancers. What’s the status of checkpoint blockade therapy in prostate cancer?
Dr. Sumit Subudhi: That’s a great question. So, in unselected patients and what I mean by unselected, those who don’t have genetic mutations that make them more likely to respond to checkpoint therapies. So, in unselected patients using a single checkpoint therapy has not been really successful in prostate cancer. Even though you are able to with example with ipilimumab or tremelimumab drive T cells into the prostate. That’s not sufficient because the prostate cancer actually has other breaks that shut down the T cells even when they come in.
So, what’s been promising is actually a combination of two immune checkpoint blockades together. For example, targeting the CTLA-4 and PD-1 pathway with ipilimumab and nivolumab respectively. And then in those settings, we’ve seen the promising response rates. And there are ongoing trials to try to test this in a larger cohort of patients that are again unselected.
Brian Brewer: Are you finding that immunotherapies may or may not be more effective based on either the age of the individual or the stage of the disease progression?
Dr. Sumit Subudhi: Yeah. Another good question. So definitely age does not seem to play a role. In fact, most people with prostate cancer are in their sixties and seventies when they’re diagnosed. And we’ve seen responses in our older patients who are in the seventies as well. So, I don’t think age is an issue. It is an ongoing question of whether or not the amount of tumor burden that a patient has… or stage. So, the lower the stage, the less tumor someone has. If someone is in stage four, they likely has a lot more tumor present.
We’re seeing responses in all stages. But again, the responses are limited and we’re hoping to combination trials or combinations with two immune checkpoint blockades or with chemotherapy or with tyrosine kinase inhibitors or targeted therapies that these responses will actually increase.
Brian Brewer: So you mentioned briefly about mutational burden and that involves some amount of genomic sequencing of tumor. Can you speak a little bit more about what that is and is it standard? Is it something that a patient needs to ask for?
Dr. Sumit Subudhi: Yeah, It’s a good question. It’s recommended. I wouldn’t say it’s a standard of care and I do believe patients need to ask for that. Patients with high risk localized cancers and all patients with metastatic cancer should be asking for it. And not just in the context of immunotherapy, but because a drug called olaparib has now been FDA approved for patients with specific mutations, in particular, the BRCA mutations or BRCA mutations that are common in breast and ovarian cancer. It’s also present in prostate cancer. And patients actually live longer if they get this.
So outside of the context of immunotherapy, I think it’s important, but also in context of immunotherapy. Because the data shows that you’re more likely to respond to immune checkpoint blockade if you have certain mutations.
Brian Brewer: Well, that’s good to hear. It’s always good to have some sort of tests, some sort of indication to help you and the patient make that treatment decision. Otherwise often or sometimes we hear if a patient doesn’t seem likely that they’re going to benefit from a therapy, you’d want to try something else. So you-
Dr. Sumit Subudhi: Yeah, I think it opens up more options. And that’s why in my clinic we do it on just about every patient because I see metastatic prostate cancer.
Brian Brewer: So you mentioned earlier, combination, combining CTLA 4 and PD-1, so ipi and nivo, which are two similar types of immunotherapy. Now you just mentioned another, sounds like a small molecule, olaparib. So that’s not an immunotherapy. So it sounds like there are many different types of combinations that may potentially be available. Can you speak a little bit more about that?
Dr. Sumit Subudhi: Yeah. That’s the exciting part, but what we’re starting to learn is that even if a drug is not an immunotherapy, such as olaparib, which is considered a PARP inhibitor, that they still have impact on the immune system, especially the immune system within the cancer itself. And that holds true for chemotherapy as well as the hormonal therapies. And so we’re just starting to better understand how these other drugs are… And these are all FDA approved drugs. And so these standard drugs, how they’re impacting the immune system. And then once we better learn that, we can develop rational combinations that will hopefully improve the efficacy of patients responding.
Brian Brewer: And with that, you’re touching on clinical trial research too and the importance there of testing these new treatments. Can you explain the difference? So, going back to 2010, a drug was approved. Actually the first kind of active immunotherapy, Provenge, for prostate cancer, which is some consider a type of vaccine or cell therapy. Are there other types of vaccines currently being studied? And if so, can you briefly let folks know what the differences between a therapeutic vaccine versus one that’s intended to prevent?
Dr. Sumit Subudhi: That’s a good question. So right now as far as prostate cancer goes, there’s only therapeutic vaccines that I know have been studied. And the one that’s already been FDA approved is sipuleucel-T, otherwise known as Provenge.
There was a study with prostate vac, which showed early promise in a randomized stage two study, where this was a vaccine that targeted PSA on the prostate cancer. And unfortunately the phase three study failed to show a survival benefit. But that drug is still not dead. And what I mean by not dead is it’s still being studied, but in combinations and hoping that it may actually benefit patients. So one of the questions is, is there a way to prevent prostate cancer? And so giving a vaccine to help prevent it the same way we try to do it with infectious diseases. That’s something that’s ongoing, but I haven’t seen any promising vaccines in that arena.
One of the most exciting vaccine approaches that I’ve seen is neoantigen vaccines. I know it’s a complicated term, neoantigen, but it goes back to the whole tumor mutational burden in a patient. So what’s happening, it’s a form of personalized medicine. So what happens in the neoantigen vaccine is a patient’s cancer is actually sequenced to identify mutations in it. And then a vaccine is made so that it can direct immune cells to actually attack those particular mutations in the patient’s own cancer. This is all experimental at this point, meaning that it’s in clinical trials. But there is a lot of promise in this approach.
Brian Brewer: Just in general, are there any clinical trials available for… One of our attendees has posted a question that her husband comes from a family with a history of both prostate and breast cancer and wonders. They’re afraid that they’re going to get cancer and he’s going to get some form of cancer and wonders, are there trials available to help prevent something like that from happening? If not, what’s the best recommended course of action that you might suggest?
Dr. Sumit Subudhi: Yeah. So I have a lot of patients who actually have prostate cancer, but they come to clinic with family members that have the same fear. And so it’s a common thing. So there was actually nothing as far as drug wise to help prevent this. But what I do recommend is early screening is important. So that means that if you have a family member at risk, at least in prostate cancer, start checking your PSA at the age of 40. And that’s a simple blood test.
In addition, I think… Not, I think, but I strongly believe healthy eating and exercise is another key. Because one of the modifiable risk factors for prostate cancer is actually being overweight or having what they call medically metabolic syndrome. And so basically being fit and healthy diet should help also prevent prostate cancer.
Brian Brewer: Well, that’s good advice all around for sure. I could certainly use some more exercise. Which gets to my next question actually. And COVID and the impact that this pandemic has had on cancer patient care. One of our viewers has written that he had to miss treatment or skip treatments for a few weeks and wonders, should he be worried? Unfortunately, he doesn’t say exactly what type of treatment he was receiving, but what are you seeing in terms of the impact of COVID on cancer patient health?
Dr. Sumit Subudhi: Yeah, so I’d like to directly first answer the patient’s question. And the truth is we don’t know and that is something that we’re trying to study in our patients on trials where their doses have been delayed and we’ll hopefully have an answer soon. But what I will say to the patient is that his immune system has been triggered and hopefully that it will continue fighting the cancer. And hopefully he’ll be able to get his next infusion soon so that he can get another boost to help kill the cancer.
Now in regard to COVID and how it impacts our patients. It’s actually, unfortunately worse. I’m seeing more of my patients being hospitalized because either their inability to come see me or travel. And as a result, the communication is not as good as it was pre COVID and they’re being hospitalized for complications related to their cancer. And especially in prostate cancer and those with bone metastasis, something called cord compression or it’s where the prostate cancer wraps around the spinal cord and if unchecked, it can lead to paralysis. But when we see early signs, we hospitalized our patients quickly to either get surgery or radiation to help prevent anything bad from happening.
But we’re seeing more hospitalizations, whereas before we could see it coming and then switch systemic treatments so we can prevent hospitalizations and prevent someone from needing radiation or surgery for this.
Brian Brewer: And what role is telemedicine playing in all of this?
Dr. Sumit Subudhi: So it’s helpful to some extent, but sometimes a physical examination is required. And especially with cord compression, that’s something that it’s hard to do over telemedicine. But no doubt, I prefer video as opposed to audio in the setting.
Brian Brewer: We have another question. Patient asking, why is it necessary to receive hormone therapy before enrolling in an immunotherapy clinical trial? I’m not sure if that’s true or not, but that’s the question.
Dr. Sumit Subudhi: No, for the most part that’s true. And when I say most part, there are some trials, but they’re few and far between where there’s not a requirement for giving a hormonal therapy. But just the rationale is because a lot of physicians have trouble putting someone on trial when there’s already a known life-prolonging therapy available for the patient. Remember these trials are experimental. We don’t know if it’s actually going to benefit the patient. And in some cases, patients can be harmed. And so a lot of people feel more comfortable putting someone on a therapy that’s been already proven. Albeit, we know that patients don’t get cured with hormonal therapies, but that’s the rationale.
Brian Brewer: And just generally, what are some of the most common questions you might get from a patient or caregiver who’s helping a patient considering receiving treatment with immunotherapy?
Dr. Sumit Subudhi: So side effects are one of the big ones. And what I tell them is that the goal of immunotherapies is to boost the immune system to fight the cancer. And as we showed in the slides, we want to change the immune microenvironment within the cancer, where we bring in more of the good cells and less of the bad immune cells.
But unfortunately the immune system can get overstimulated and start attacking any part of the body that includes the skin, which can lead to a rash. It can attack the colon and lead to diarrhea and or it could in fact, it can attack the eyes and cause temporary blindness. So these are serious things. I know people may say, oh, diarrhea is not a big deal, but it actually… I’ve had a patient lose 35 pounds in three days from the diarrhea. So this is not just a little bit of diarrhea.
But what is key is communication between the medical team and the patient. Because once you have these early signs, then there are measures that we can take medically to help prevent bad things from happening. In fact, I was at a wedding yesterday evening when a patient called me to tell me that he was having a rash that went all over his body. And so we medically intervened and he’s doing well today. So he prevented a hospitalization. And if he didn’t tell me, then most likely the patient would have been hospitalized by Monday. So I think having good communication is important.
Brian Brewer: Very important. We’ve heard that over and over again, both during yesterday’s sessions and then during today’s breakout session. So again, super important for patients to… And no matter what’s happening, anything could be as a symptom of your treatments. So it’s important to communicate that to your doctor. So thanks for bringing up that point. We have another question from someone who has had his prostate removed and has received, I guess, chemotherapy and even radiation therapy prior to that. Does that make this person ineligible for immunotherapy or could immunotherapy still be a potential treatment?
Dr. Sumit Subudhi: Yeah, so the only immunotherapy that’s FDA approved right now is sipuleucel-T, otherwise known as Provenge. And that is given for patients who are castration resistant. And so what that means is, many patients have shots that are given, hormonal shots that help lower their testosterone. And when those shots are no longer sufficient in controlling the cancer, that’s where Provenge is FDA approved for asymptomatic and minimally symptomatic patients. So it doesn’t matter whether you had chemotherapy or not. You just have to have a PSA that’s increasing while on the shots.
But in regard to a bigger question is that there are a lot of immunotherapy trials right now going on in prostate cancer. And every trial has different criteria. Some trials don’t allow for prior chemotherapy and some do. And so that’s something that just has to be addressed on a trial by trial basis.
Brian Brewer: So you brought up PSA, which is a term many people are aware of when learning about prostate cancer. And in this case, it was required to have increasing PSA in order to be eligible to receive a certain type of treatment. Do you see any correlation between PSA level and patient responses to immunotherapy?
Dr. Sumit Subudhi: Yeah. So in regards to Provenge vaccine, I do see that. In fact, the lower the PSA when you get the Provenge vaccine, the more likely you will not need to go onto another therapy for a while. So for example, I have a few patients in my clinic that have not needed another therapy for two to three years after getting Provenge. But all of these patients had low PSAs. when I say low, less than five when they received Provenge. But in regards to immune checkpoint therapies, which are again in clinical trials, we’ve seen people with PSAs of 500 respond and go all the way to zero. So I don’t see a correlation with immune checkpoint therapies.
Brian Brewer: Going back to, since most of these treatments are still considered investigational and not FDA approved for this type of cancer, do you see any difference in treatments that are administered systemically? So IV drip versus those that are injected directly into tumors, is there anything happening there?
Dr. Sumit Subudhi: That’s a great question. That’s something that’s relatively new. These intratumoral injections of immunotherapies or even chemotherapies. And so the data is still early. So we don’t know if that’s actually a benefit. It actually makes sense that intratumoral injections would be more beneficial for a patient because you will have less of the side effects. But we also have to remember that most patients, at least patients with metastatic disease, have more than one or have several places where they have cancer. And it’s impossible to inject into all those places. So it’s something to keep in mind. So I think that the intratumoral injections may be more beneficial for those with localized prostate cancer, where it’s only in the prostate and it’s not spread. But we’ll see.
Brian Brewer: Is that any way related to the tumor microenvironment that you mentioned earlier. Are those related or is that something completely different?
Dr. Sumit Subudhi: No, it actually is related. And it’s a great point because I think one of the most exciting areas of research now is looking at the different prostate tumor microenvironments. And what do I mean by different is you have the primary prostate cause that’s where it started. And so that’s one microenvironment, but a majority of patients with metastatic disease, approximately 70 to 80%, have it in their bones. And we’ve learned that the microenvironment in the bones is different from the primary prostate. And then another approximately 50% of patients have it in their lymph nodes. And so that’s a different microenvironment. And finally, 6% of patients have it in liver and other organs such as the lung. And again, we’ve seen that there’s a different immune microenvironment there.
So what does that tell me? It tells me that we need to start better understanding how our current drugs, like I said, chemotherapy, hormonal therapy, impact each of those microenvironments. And then how can we use rational combinations with immunotherapies to try to overcome the immunosuppressive microenvironment that’s present?
Brian Brewer: Can someone remain on an immunotherapy indefinitely or is it a finite period of time?
Dr. Sumit Subudhi: Yeah, so the answer is, I hope you don’t have to be on it indefinitely because our goal is like the same thing as you have with an infection, where you’re trying to prevent an infection with a vaccine. You don’t get a vaccine for measles every single day or week or once a month. It’s because your immune system has developed a memory from that vaccine. And so in the same way, we hope that our immunotherapies can be given for a finite amount of time so that you don’t need it forever because your own immune system will get boosted and have a memory for the cancer. And so anytime the cancer comes back, it’ll be able to fight it.
Brian Brewer: So this is a personal question for you, really, was immunotherapy always part of your practice or did your practice in the way that you treated prostate cancer patients changed once immunotherapy started becoming what it is today? And if so, how?
Dr. Sumit Subudhi: Yeah, that’s a great question. So the truth is my mentor is Jim Allison and he’s the reason why I think about immuno therapy so much. And so I was in prostate clinic, but also working in his lab. And many of you may know, he won the Nobel Prize for his work with immune checkpoint therapies or immune checkpoint blockade. And he himself has luckily been cured from prostate cancer, but unfortunately he lost his brother to prostate cancer. And so it’s something that’s really meaningful to him. And when I was training, I was frustrated that we didn’t have anything to cure our patients.
We have a lot of drugs in prostate cancer, but none of them cure. And so I found or I saw the potential for immunotherapies to actually provide cure for patients who have metastatic or incurable prostate cancer. And I can tell you, it’s amazing when you do succeed in curing a patient that is considered incurable. But unfortunately it’s happening too far and few. And we need to find ways to make it so a majority of our patients, if not all of them, are being cured.
Brian Brewer: There’s definitely a lot more work to be done there. We’re coming down to the wire here in terms of time. We have a few more questions, but I’d just like to remind our viewers to please submit your questions, excuse me, to the Q and A. And even if we can’t get to them all today, we’ll be sure to follow up with as many as possible in a blog post later on. Dr. Subudhi, what are BiTEs, bi-specific T-cell engager therapies. Can you explain to us what they are and are they applicable in prostate cancer?
Dr. Sumit Subudhi: Yeah, that’s a great question. So if you remember one of my slides where I said that there’s very few T cells in the prostate. And we’re always trying to figure out how can we drive more T-cells in there? And so what BiTEs do it’s actually has two targets and they’re linked together. That’s why they’re bi-specific. And one target recognizes something on the prostate cancer itself, a protein such as maybe PSMA is a common one or PSA. And the other one recognizes something on the T cell, whether it’s a protein called CD3 on a T-cell or CD28 on T-cells.
So what it does is, it will first bind to immune cell that’s in your blood and then it will find the cancer and latch onto the cancer. So in that way, it’s bringing the T cells right to the cancer. So that’s how it works. There are clinical trials that are going that we’re actually actively playing a role in with BiTEs. And not just with bites alone, but BiTEs combined with immune checkpoint blockade, which I think is actually a really promising approach. So you have a sophisticated group or we have a sophistic group of audience, of prostate cancer patients that actually are aware of these new technologies.
Brian Brewer: Well, many of them watched our sessions yesterday where we went over the basics of immunology immunotherapy. So yeah, everyone’s getting mailed a PhD. So that’s good. So we have a minute left and I just want to come back to clinical trials. Since this is where a patient is going to encounter an immunotherapy right now most likely for prostate cancer. Can you just say a few words about why they’re important and how they’re helping and what are we learning from them and how’s that going to advance reception?
Dr. Sumit Subudhi: So, first thing, I think it’s important for patients to ask their physicians about what clinical trial options are available. And I actually tell my patients that I’m not married to MD Anderson in the sense that if there’s an exciting clinical trial elsewhere, I will share that information with them and help them actually get to where they need to go for that. In fact, I sent 17 of my own patients last year to institutions because I felt like they had different clinical trials than what I had to offer in our institution. And I thought those trials suited them better. So that’s one thing. So I think asking is important.
Now, enrolling in a trial, I want you to know is an experiment. Even though it’s exciting, we don’t know if it’s actually going to benefit. We hope it does. And I think a lot of patients have concerns of whether they’re going to be on a trial that they’re guaranteed to get the immunotherapy or they’re going to get a placebo. And I tell patients, don’t worry about the placebo, because you’re still being watched so carefully that we will switch you to something more effective if you end up with the placebo.
So you don’t have to be worried about getting harmed, but what you should ask your doctor, if they are considering you on a trial where you may get a placebo, ask them what their backup plan is. What happens if I do progress? Do you have another immunotherapy trial for me or what standard therapy are you planning? I think it will help alleviate some of the anxieties. The other thing in clinical trials, I believe our patients are taking a risk and therefore they’re brave and they’re courageous. They’re helping us innovate the future. And what we’re learning, because many of these trials require biopsies and extra blood collection so we can look at the immune system and how it’s being impacted by the drugs we’re giving, it’s actually leading us to develop even better trials. So the truth is the patients who did the ipilimumab monotherapy trials, we learned from those trials that yes, that monotherapy wasn’t enough for most of the patients, but we also learned why it wasn’t and that as a result, now we have combination trials that have come out of it. So I’d like to thank our patients who volunteered in this process.
Brian Brewer: Well, that’s a great way to wrap up by thanking patients and remembering the important role that they play in all of this as well. And anyone else wanting to learn more about clinical trials, please view our session from yesterday with Dr. Ezra Cohen, who goes into more detail about what they are. But Dr. Subudhi, thank you again so much for joining us. Please continue submitting questions in the Q and A. And I look forward to seeing some of you at the next session.
Dr. Sumit Subudhi: Thanks.
Tamron Hall: Thank you, Dr. Subudhi, for the informative and helpful discussion. Dr. Subudhi will be answering many of your unanswered questions in the upcoming weeks on CRI’s blog. So please stay tuned for more. And we’re going to take a short break. In the meantime, we invite you to set up a free and confidential consultation with one of CRI’s clinical trial navigators. To schedule your appointment, please email us at email@example.com. We also encourage you to explore resources from our partners during the break, which are all located in the CRI resource guide. Thank you again. And we’ll be right back.