Conversations With Prostate Cancer Experts

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Dr. Fatima Karzai is the Director of the Prostate Cancer Clinic for the Genitourinary Branch at the National Cancer Institute. She’s keenly interested in developing novel strategies for harnessing the power of the immune system for hormonally driven cancers, particularly in advanced prostate cancer.

Prostatepedia spoke with her about a clinical trial she’s running that combines PARP inhibitors and a class of immunotherapeutic agents called PD-L1 inhibitors in men with advanced prostate cancer.

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Why did you become a doctor? What is it about medicine that keeps you interested?

Dr. Fatima Karzai: I decided to become a doctor at a very young age. I’ve always wanted to help people. When I was younger, I thought that being a doctor was the best way to do that. I really enjoy patient interactions, so that’s why I’m a clinical researcher and I see patients on clinical trials. I find that it’s the most rewarding experience to be able to interact with patients. It’s always been a goal of mine to be able to help people in this manner. I think oncology was best suited for me to do so.

What are PARP inhibitors and PD-L1 inhibitors? How do they work, in which patients are they used, and how effective are they?

Dr. Karzai: PD-L1 inhibitors are members of a group of drugs called checkpoint inhibitors that have been developed for the treatment of cancer. PD-L1 is a protein that is present on the surface of cells. In cancer, PD-L1 on the tumor cells interacts with another protein on a person’s white blood cells, which are immune cells that help fight cancer. This PD-L1 protein prevents the immune system from attacking the tumor cells. A PD-L1 inhibitor blocks that ability of the tumor cell to suppress our immune system, which can help our immune system kill cancer cells. They’ve been successful in certain cancer types like lung cancer and bladder cancer.

PARP inhibitors are a type of targeted therapy. We all have DNA in our bodies; when it becomes damaged, our bodies know how to repair it. Many things can cause DNA damage: exposure to UV light, radiation, or substances in the environment. There is an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. By blocking PARP in cancer cells, we can keep cancer cells from repairing their damaged DNA, which causes them to die. PARP inhibitors work very well in a subset of patients whose tumors harbor something called “DNA damage repair mutations.” These mutations can occur in the tumor itself or it could be something that a patient is born with. PARP inhibitors were initially studied in ovarian cancer and breast cancer. We’re starting to use them more in prostate cancer.

What is the rationale between combining the two agents for prostate cancer?

Dr. Karzai: We wanted to expand the use of PARP inhibitors. Like I mentioned before, right now they’re used in patients with these specific mutations. We’re trying to figure out if we’re able to get this class of drugs to work in patients without these mutations if we combine them with another drug. Historically, PD-L1 inhibitors have not been that successful in prostate cancer, so we decided to put these two drugs together to see if there is any additive or synergistic mechanism that could help patients with advanced prostate cancer.

What have the studies revealed about the combination?

Dr. Karzai: We are still accruing to the study. We’ve looked in-depth at the first 17 patients and seen deep and prolonged responses in men with castrate-resistant prostate cancer with the combination, in men who have these germline or somatic DNA damage repair abnormalities. We’re now adding additional patients to the study to better define the activity and to help us evaluate the biology more.

You said you’re still looking for more patients?

Dr. Karzai: Correct.

Tell us a little bit more about eligibility criteria and who men can contact if they think they’re a fit.

Dr. Karzai: We are looking for patients with advanced prostate cancer—i.e. the prostate cancer has gone outside the prostate and is in either the soft tissue, organs, and/ or bones. We would like to have these patients previously treated with either Zytiga (abiraterone) or Xtandi (enzalutamide). We think patients who have progressed on these two treatments might be more amenable to our combination. We allow previous chemotherapy, so if a patient has had Taxotere (docetaxel) or some other chemotherapy, they would be eligible. We are looking for patients who are still able to perform their activities of daily living and would be willing to participate in our trial and travel.

Some of our patients are local, but many come from across the United States. We even have some international patients.

You help defray the cost of travel for some of your clinical trial participants, don’t you?

Dr. Karzai: We do. Once a patient is on one of our protocols, then we reimburse flights in the United States. We also have a stipend for meals and hotels.

Any further thoughts on this particular combination or other combinations that you think may hold promise?

Dr. Karzai: Even though this type of immune therapy hasn’t been very successful thus far in prostate cancer, I still think that we need to do more studies and research to be able to find the subset of patients that it might work in. Immunotherapy is very exciting. We shouldn’t count it out in prostate cancer yet. The first vaccine that was FDA-approved in cancer was actually for prostate cancer. I think that the whole realm of immunotherapy is still open and could provide benefits for our patients. I am happy to see any patient for a consultation —those with newly diagnosed disease or those who are more advanced. We have clinical trials that span that spectrum of prostate cancer.

Join us to read about more immunotherapy clinical trials for prostate cancer.


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Combining Keytruda (pembrolizumab) and Xtandi (enzalutamide) For Prostate Cancer

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about her continuing work on combining Keytruda (pembrolizumab) with Xtandi (enzalutamide).

What are Keytruda (pembrolizumab) and Xtandi (enzalutamide)? How and when are they used in prostate cancer patients?

Dr. Graff: Keytruda (pembrolizumab) is an intravenous antibody to PD-1 or programmed death 1 on immune cells, in particular T cells. When that protein is present, it can interact with tumor cells that have PD-L1 and through that interaction the tumor cells turn off the immune system. We consider it a checkpoint inhibitor.

We’ve known for a long time that in some cancers T cells, which are the part of the immune system that can kill cancer cells, are present in the tumor and yet they’re not actually killing the tumor. Over the decades we’ve learned that some of those cells, not necessarily T cells but immune cells in the environment, are actually helping the tumor grow. We’ve also learned that some of them are trying to fight the tumor, but they’re being turned off by the tumor.

Keytruda (pembrolizumab) can block that negative signaling, thereby activating the immune system. It was first approved in melanoma and has received multiple subsequent approvals. So far we don’t have great markers for knowing who will benefit from the drug and who won’t, but we are working on that.

Xtandi (enzalutamide) is a drug that binds to the androgen receptor, which is inside the prostate cancer cells, and prevents it from interacting with androgens or male hormones. In that fashion, it leads to some cell death and helps people live longer. It’s been FDA approved since 2012 in the post-chemo setting, and now it has been approved in the pre-chemotherapy setting. It used to be approved only in metastatic disease, and now it’s approved in non-metastatic castrate-resistant disease. It’s being applied in different stages of the disease.

What is the rationale behind combining these two agents?

Dr. Graff: In studies where checkpoint inhibitors like Keytruda (pembrolizumab) are used alone, there’s not a lot of tumor activity. There’s certainly not a good rationale to use Keytruda (pembrolizumab) by itself in prostate cancer. Maybe as time goes on we’ll find that perhaps 2 out of 100 patients have certain mutations that make the Keytruda (pembrolizumab) alone helpful, but we’re not yet there.

There wasn’t a great reason to use Keytruda (pembrolizumab) by itself, so we began to think about combinations. Xtandi (enzalutamide) was felt to upregulate PD-L1 on dendritic cells, in particular when people became resistant to the Xtandi (enzalutamide), so that was one initial reason.

Castration therapy may reinvigorate the immune system. When you’re maturing as a child, you have a thymus gland behind your sternum that helps create new T cells. As you go through puberty, that gland shrinks and becomes inactive, so you don’t make new T cells.

It looks like maybe the thymus increases again during castration therapy; there’s a hypothesis that you’re creating new T cells.

There is also a reason to think about Xtandi (enzalutamide) in particular. It’s helping in those two regards.

Also, if you used Keytruda (pembrolizumab) in combination with chemotherapy, you would be at risk of killing a lot of immune cells with the chemo itself. If you used Keytruda (pembrolizumab) in combination with Zytiga (abiraterone), which is like Xtandi (enzalutamide), you would have to use prednisone, which would perhaps dampen the immune response. When our study was designed in 2014, it made a lot of sense to combine Keytruda (pembrolizumab) with the Xtandi (enzalutamide).

What have studies revealed about the combination? Is it effective? What kind of side effects do patients experience?

Dr. Graff: We did a Phase II study looking at 28 patients with metastatic castrate-resistant prostate cancer whose cancers were progressing on Xtandi (enzalutamide). We added 4 doses of Keytruda (pembrolizumab). We saw 5 responded in that group of 28. That’s only 18%, but when they responded, they responded spectacularly.

The most extreme case was a gentleman who started out with a PSA of 2,500 that went down to 0. He had big, bulky liver tumors that just shrank away. He must be two and a half, almost three years out from treatment and he’s still in complete response. His case is extreme. But when we do see responses, they’re spectacular.

If those five patients had only had a dip in their PSA or something less impressive, the study wouldn’t be as important as it was. Then we had four other people who had very durable responses as well. That’s the benefit part of the study.

But there are known side effects with each of these drugs. With Keytruda (pembrolizumab), when you stimulate the immune system you run the risk of the immune cells killing or attacking healthy tissue. For example, a patient on Keytruda (pembrolizumab) could develop autoimmune hepatitis where the immune cells are attacking a healthy liver. There are some bad sides to stimulating the immune system.

In our study, we did see some of those side effects. In these 28 patients who were treated, we did have patients who had autoimmune toxicities in which their own immune cells attacked healthy tissue. We had four patients who had thyroid dysfunction, which is a fairly well recognized side effect of Keytruda (pembrolizumab) that is easy to manage with thyroid medicine. We had a couple people with colitis, which happens when the immune system attacks the colon; that has to be managed with high-dose steroids and sometimes biologic drugs that GI specialists use. We saw side effects that we would expect from Keytruda (pembrolizumab) and we saw some side effects that we would expect from Xtandi (enzalutamide) such as fatigue. Since these patients had already been on Xtandi (enzalutamide) for a long time, we did not observe worsening of the Xtandi (enzalutamide) side effects with the addition of Keytruda (pembrolizumab). We mostly just saw those Keytruda (pembrolizumab) side effects.

Any follow-up studies planned?

Dr. Graff: We got funding from Merck to add another 30 patients on to that study. Those 30 have already been enrolled and treated. For those patients, we insisted on a biopsy. For the first 28 patients, we asked them to get a biopsy if they had a tumor that could easily and safely be biopsied. In the next 30 patients, we required that they have a biopsy. We have now a nice array of tissue from these 58 patients and we’re working on getting the results. We have some multiplex stains and hope that the paper can come out next year.

Join us to read about another of Dr. Graff’s clinical trials that will be accepting patients shortly.

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Prostate Cancer Vaccine Clinical Trials

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Prostatepedia spoke with him recently about ProstVac and open prostate cancer vaccine clinical trials.

There is a vaccine that was under investigation called ProstVac. Can you tell us a little about that vaccine and whether or not it has been effective? 

Dr. Gulley: ProstVac is a pox viral-based therapeutic vaccine that has the genes for PSA, as well as three different human T-cell co-stimulatory molecules. What that means is that the vaccine is something that we can give that can train the patient’s immune system to recognize and attack cells that make PSA. Normal prostate cells or prostate cancer cells can make PSA. There are cancer patients who have had their prostates removed. The only cells left behind that would express PSA are the cancer cells.

There are two basic viruses that are used. One is vaccinia for the initial vaccine. It’s a really good jolt to the immune system. All the subsequent boosting vaccines are given with fowlpox that again contain the same genes for PSA and co-stimulatory molecules. That can continue to boost an immune response.

There were initial studies done with this agent that showed that it was safe to give in patients with advanced cancer and that when given it could generate immune responses to PSA in those patients. If you took cancer cells with the immune cells from those patients, those immune cells could recognize and kill those cancer cells that make PSA.

We then did additional studies looking at this activity, including one randomized Phase II study that was double-blinded. 125 men received vaccine versus placebo. In that study, we found that there was no difference in progression-free survival, but there was an improvement in overall survival, which was our secondary endpoint.

This is very similar to what was seen with Provenge (sipuleucel-T). So we followed this up with a larger study to confirm whether or not these findings are correct. We embarked on a 1,200-patient study that over enrolled. There were 1,297 patients enrolled on that study. We presented the results at the conference of the American Society of Clinical Oncology in 2018: there was no improvement in overall survival with the vaccine.

I should mention a little bit about the trial design. There were three arms in the study: one group received the vaccine plus GM-CSF. This was used in the Phase II trial and showed an improvement in survival. GM-CSF, or Granulocyte-macrophage colony-stimulating factor, can further boost immune response. We don’t know if it is required for the vaccine or not. Interestingly, because of the difficulty in getting this outside of the United States and because we didn’t know if it was needed or not, we did one arm with GM-CSF and another with no GM-CSF. The third arm got a placebo. The placebo vaccine was just comprised fowlpox vector.

What we saw in that study, which showed no improvement in survival, is that we don’t really have a clear explanation of what happened or why we saw a difference in the Phase II study. It could be that the Phase II study was just under-powered and the results we saw were based on chance. (I’m just going to lay everything out here.) It could be that the vaccine was effective and that it did generate immune responses, but that those immune responses did not translate into improved survival for a variety of different reasons.

First, multiple agents have been approved since the initiation of the drug; Zytiga (abiraterone), Xtandi (enzalutamide), Jevtana (cabazitaxel), Xofigo (radium-223), and Provenge (sipuleucel-T) were all approved after that study was designed. It’s possible that when these agents are used afterwards they delete out any treatment effect.

If you look at the overall survival data from Xtandi (enzalutamide) and Zytiga (abiraterone), you’ll see huge improvement in survival in the post chemotherapy setting. In the pre-chemotherapy setting it’s very difficult to see an improvement in survival. In fact, there was no statistically significant improvement in survival with Zytiga (abiraterone) in the pre-chemotherapy setting, suggesting that that could be another explanation for why an improvement in survival just wasn’t seen. The lines are really overlapping. Finally, it could be that the vaccine was generating an immune response. That immune response went to the tumor, but those cells were held in check because of regulation of PD-L1 or something like that. It turns out that when you have activated T-cells that recognize a tumor, they make gamma interferon and cause the other T-cells there to recruit other cells, but that gamma interferon will cause up-regulation of PD-L1. (PD-L1 is a stop sign to T-cells.)

As soon as the T-cells see that stop sign, then they stop everything and they can’t do anything while that’s there. If you come in with an immune checkpoint inhibitor and block either the PD-1 or the PD-L1, you basically cover that stop sign and those T-cells go back to work.

Perhaps that is what’s going on. We did a study in the neo-adjuvant setting where we gave a ProstVac vaccine to patients undergoing surgery. We did see immune cells getting into the prostate, but often not into the tumor, so it may not just be the PD-L1. There are other things excluding the T-cells from the tumor, for example there may be no HLA-A2 expression. Maybe there is up-regulation of TGF-beta. These are still things we’re grappling with, things we’re trying to understand. We’re also trying to come in with other clinical studies to address these different aspects of what might be going on in the tumor microenvironment to lead to a better outcome.

You’re still looking for explanations?

Dr. Gulley: Correct. There are ongoing studies looking at ProstVac in men with a biochemical recurrence. There are ongoing studies in active surveillance—with patients who don’t need treatment.

There are ongoing studies in combination with other agents, like ProstVac and Opdivo (nivolumab). We’ve looked at that combination in men with metastatic disease. I mentioned earlier two of the twelve patients had good responses. Ten of them didn’t. We’re trying to understand that better, so we’re taking it into the neoadjuvant setting. We’ve enrolled one out of the seventeen patients we need to understand a combination of a vaccine plus Opdivo (nivolumab). We’re getting biopsies and comparing that with the prostatectomy specimen to see if there is an increase in immune cells. Do we get more of an increase in immune cells from that combination than we get from the vaccine alone? How do we improve upon that?

If a man reading this is interested in joining a trial, there are multiple options for him to consider?

 Dr. Gulley: Absolutely.

Join us to read about additional trials that Dr. Gulley and his colleagues are running.


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Who Is Dr. James Gulley?

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Join us to read Dr. Gulley’s comments about prostate cancer vaccine clinical trials.

Why did you become a doctor?

Dr. James Gulley: I think this has to go back to my high school biology teacher. His name was Vernon McNeilus. He was a retired orthopedic surgeon who just found a way to instill inspiration and that sense of curiosity about life. He drove us to really be excited and interested in science and in biology in particular. I had decided that I wanted to do something in science or medicine, but there was no way that I was going to go spend all that time to become a doctor. I’d been in school long enough. One of my friends decided he was going to go into medicine. I said if he can do it, I can certainly do it.

Then it actually evolved even further than that because during my stint in college I got the opportunity to do a summer research program. I decided I liked research, so I applied to MD/PhD programs and got accepted into two. I decided to go to Loma Linda.

What is it about medicine that keeps you interested?

Dr. Gulley: I think the thing that really drives me is how fascinating it is to understand how things work. I’ve always been fascinated in what makes things work. As a little boy I would take things apart trying to figure out what made them work and then put them back together again. If something was broken in the house, my mom would just give it to me and I’d tinker with it and get it to work again.

To me, the ultimate machine is the human body and one serious puzzle is to figure out ways to bring back health from sickness. Not just a puzzle for curiosity’s sake, but because of the effect that cancer can have on families, to uncover ways to effectively treat cancer. I think it’s truly something that I have seen patients who were close to death who have had remarkable and prolonged clinical responses. That, to me, begs the question that if we can do it for some people, then why can’t we do it for all people? That is what I am passionate about.

Are there any patients you’ve had over the years whose cases changed how you see your own role or the art of medicine?

Dr. Gulley: I’ve had several patients that have been exceptional responders; that really has changed how I view things. One of my more recent exceptional responses from this past year is a retired army surgeon who has advanced metastatic castrate resistant prostate cancer. I have been treating him since 2005. He was initially treated with radical prostatectomy. It turned out that he had a high Gleason disease. He had radiation therapy, but he had recurrence of his disease, unfortunately. He was treated with hormonal therapy, with chemotherapy, with Provenge (sipuleucel-T), and Xtandi (enzalutamide).

He came to me last year having had multiple therapies including other experimental immunotherapies. He was clearly not doing well. His PSA was going up very quickly with a doubling time of less than a month. His symptoms were getting substantially worse. He articulated to me that even going to church every week was becoming difficult: one week he was able to sing the songs and the next week he was too tired to sing. Then the next week he was almost too tired to stand up.

We were able to enroll him in a study combining a vaccine with checkpoint inhibition. When we gave him that combination, his PSA dropped dramatically. It has now gone to undetectable. His lesion in his bladder, which was causing local symptoms so that he had to have a chronic indwelling Foley catheter, shrunk away. When we biopsied it there was no evidence of tumor there. He has some lesions that are seen on bone scan, but I’m not sure if that represents viable tumor or not.

He is now over a year out from when he started treatment. His energy level hasn’t been better since before he was diagnosed. He is out doing everything he wants to do. To me that is amazing. It is amazing we can see responses like that.

From a scientific standpoint, of course, I was stunned to see this and wondered could he have micro-satellite instability that leads to lots of mutations. It turned out that he had micro-satellite instability in his cancer, suggesting that the immune system was able to see his cancer much more readily, so all we need to do is allow those immune system cells to be functional with the Opdivo (nivolumab).

We also had one other patient that didn’t have micro-satellite instability with this combination who also had a really nice 90% or so drop in his PSA. It’s not undetectable, but he hasn’t had the immune checkpoint inhibition for well over a year now. He’s just on vaccine alone because he had some bleeding in his urine from the checkpoint inhibitor. To me, having responses like that changes my outlook. It says the immune system, even in patients with prostate cancer, can be harnessed to attack the tumor. We just have to figure out ways that we can make this more applicable to all patients.

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Immunotherapy For Prostate Cancer

In January, we’re talking about immunotherapy for prostate cancer. Dr. Charles Myers introduced the issue for us.

Not a member? Join us to read this month’s conversations about immunotherapy.

The goal of this issue is to capture the current state of the art in immunotherapy of prostate cancer. We live in a time when immunotherapy is making major contributions to the treatment of many malignancies. The Nobel Prize was recently awarded for the discovery of checkpoint inhibitors that have revolutionized the treatment of melanoma. Chimeric antigen receptor T (CAR T) cell therapy represents a major advance in the treatment of B-cell lymphoma.

Unfortunately, immunotherapy has not yet had such a dramatic impact on prostate cancer treatment. The Provenge (sipuleucel-T) vaccine has been approved for prostate cancer treatment because it results in a modest improvement in the survival of patients with advanced disease. The checkpoint inhibitors have not shown useful activity in prostate cancer, although a small group of patients have had dramatic responses. The current situation may be best summarized by saying that immune response to prostate cancer can be demonstrated in patients, but various factors appear to limit cancer cell kill.

In this issue, we feature conversations with investigators who are doing interesting research on how to overcome factors limiting the effectiveness of immunotherapy in prostate cancer.

Dr. Charles G Drake talks about the state of immunotherapy in 2018 and looks ahead to what we can expect to happen in 2019.

Dr. James Gulley talks about why the initial trials with the prostate cancer vaccine ProstVac didn’t prove as promising as we’d all hoped. He also outlines a number of prostate cancer vaccine clinical trials looking for patients.

Dr. Julie Graff discusses clinical trials—both completed and those looking for patients—that combine Keytruda and Xtandi.

Dr. Fatima Karzai tells us about clinical trials at the National Institute of Health that combine PARP and PD-L1 Inhibitors.

Dr. Bruce Brown, Chief Medical Officer of Dendreon, discusses a clinical trial that looks at using sipuleucel-T in men on active surveillance.

Each conversation this month includes information on clinical trials that are recruiting prostate cancer patients. If you think you may be a fit, please don’t hesitate to contact the investigator.

Join us for more information.

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Dr. Charles Drake On A Memorable Patient

DRAKE charlesDr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center.

Dr. Drake discusses a patient whose case intrigued him.

Have you had a particular patient who changed how you approach your work?

Dr. Charles Drake: Absolutely. I had a gentleman who had metastatic, castrate-resistant prostate cancer. He had been treated with hormonal therapy. He was about to go on chemotherapy. He had progression in his bone lesions, but he developed hematuria.

On CT scan, there was a fairly clear lesion in his bladder. We couldn’t tell what it was just by the scans, and his PSA was doubling quickly, it had reached 30 or so in less than a couple of months. We sent him to Dr. Ronald Rodriguez, who was at Johns Hopkins at the time, and he thought it looked like this was probably metastatic prostate cancer invading the gentleman’s bladder. Dr. Rodriguez did a transurethral fulguration, meaning he burned all of the tumor he could find in the bladder. After the procedure, he told me that there was a fair amount of prostate cancer left behind. While the procedure went well, and he got most of the tumor, he didn’t get all of it.

What happened next was fascinating. The patient’s PSA dropped. His PSA went from 30 to 20 to 10. It eventually nadired, or reached its lowest point, at less than 1 ng/ ml and he remained in remission for nearly two years. Although clearly anecdotal, in my mind, there is almost no question that this was one of those anecdotal abscopal responses, which makes you believe that it can happen. Almost certainly that was what happened for this patient. I’ll never forget it, frankly.

Interesting. An unexpected systemic response from local treatment, right?

Dr. Drake: Yes. It was brilliant. Just by treating the local disease in the bladder, this gentleman did well for over two years before it apparently progressed again, and he wound up getting chemotherapy. He also did very well with the chemo, so in my hopeful view, that suggests that maybe this fulguration procedure sparked a systemic immune response.

Join us to read the rest of Dr. Drake’s comments on the elusive abscopal effect.

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The Genomic Revolution Comes To Prostate Cancer

Dr. Oliver Sartor, the Laborde Professor of Cancer Research in the Medicine and Urology Departments of the Tulane School of Medicine, is one of the leading researchers in advanced prostate cancer today. He is also the editor-in-chief of Clinical Genitourinary Cancer and the author of more than 300 scientific papers.

Dr. Sartor puts this month’s conversations about prostate cancer genomics into context for us.

“We can divide genomics into two different categories. The first category is germline genomics, which is the DNA with which you’re born. It’s clear that about 12% of people with advanced prostate cancer will have alterations in their inherited DNA, in particular in genes involved with DNA repair. Most common of these alterations are BRCA2. There are a variety of others that are somewhat prevalent, including ATM, CHEK2, and BRCA1. There are others that are more rare.

The implications of these germline mutations are significant for the patient: in certain configurations they may predispose a cancer to be sensitive to certain therapies, such as PARP inhibitors or platinum-based chemotherapy or (rarely) immunotherapy. There is more complexity, but knowing the germline mutation helps the informed clinician make decisions. In my practice, we test all patients with advanced prostate cancer for these germline mutations. (A National Comprehensive Cancer Network guideline suggests the same approach.)

These germline mutations represent the DNA with which you’re born. That DNA is going to have repercussions if also mutated in your family members. Men who have some of these DNA repair mutations have an increased risk of prostate cancer. In addition, there is a small increased risk of pancreatic cancer and male breast cancer for those with some of the germline mutations. Around 30% of men with BRCA2 will be diagnosed with prostate cancer in their lifetime, but that cancer is more likely to be aggressive if diagnosed. With regards to females, it’s particularly important. Females with DNA repair defects are more likely to have breast and ovarian cancer. Female with DNA repair mutations, in particular BRCA1/

BRCA2, ought to consider having their breasts or ovaries removed at an appropriate time. Prophylactic surgery has been demonstrated to be potentially life-saving for those individuals. The risk of breast cancer may be as high as 70% and the risk of ovarian cancer may be as high as 40%.

Thus, for these germline mutations there are implications for treatment and implications for the patient’s family.

We should be doing prostate cancer screening earlier in men with these DNA repair defects for prostate cancer; we should be doing biopsies at a PSA of 3 or higher, and perhaps even lower, for younger men known to be at risk. Starting screening at age 45 has been suggested by some. In addition to germline genomics, we need to also talk about somatic genomics. Data indicates that about 60% of individuals who have a DNA repair germline mutation are likely to have another second genetic mutation occur within their tumor. In addition, many of the tumors can acquire an alteration in their tumor DNA even when the germline is normal.

Taken together, about 20 to 25% of men may have DNA repair mutations in their tumor’s DNA. That makes them particularly sensitive to certain therapies such as the PARP inhibitors, as I mentioned earlier, or platinum chemotherapy. When you have two DNA repair mutations in the same cell, the likelihood of response to these agents appears fairly high.

There are also other DNA defects of considerable interest, such as alterations of the mismatch repair genes MSH-2 and MSH-6. When these alterations do occur, there is a potentially increased probability of responding to immunotherapy such as the new PD-1 inhibitors.

Overall, the guiding light today in genetics in my practice is to look at both the germline DNA and the tumor DNA. I choose to look at the tumor DNA circulating free DNA (cfDNA) tests, in particular the Guardant Health assay. The ability of other assays to corroborate the Guardant Health findings is not yet clear. There is clear data to indicate that different assays give different results, but nevertheless, I think in the early exploratory phase we’re in now, it’s important to begin to test patients in order to better understand their genomics and hopefully guide us towards better therapies. This will happen part of the time but certainly not all of the time.

There is more to the story of prostate cancer genetics. We’ve looked at androgen receptor mutations that can have implications for a response to Androgen Receptor directed therapy, such as Xtandi (enzalutamide), Zytiga (abiraterone), and Erleada (apalutamide). We’re dissecting a number of permutations that occur. It’s a complex scenario, because very few men have only one mutation. Most have multiple mutations. And in most cases, these mutations are not targetable with current therapies. This is very important for people to know.

Everybody thinks if they get a genomics test that means they’ve got a treatment. It’s not the case. Many times we get the genomics results and find that there are no known treatments we can use for that man’s particular alteration. That said, there is a subset of men who will have informative genomics while many more people will have non-informative genomics.

There is a final issue I’d like to discuss. There is currently a bit of a debate amongst physicians over the utility of PARP inhibitors such as Lynparza (olaparib) as compared to platinum chemotherapy. But it is noteworthy that platinum-based chemotherapies are inexpensive compared to PARP inhibitors. This does not require a clinical trial. (Most men will access PARP inhibitors through a clinical trial, although sometimes insurance companies are willing to try.)

As it turns out, neither the platinum-based chemotherapies nor the PARP inhibitors will be effective forever, so we do need strategies to manage patients after PARP inhibitors or platinum-based chemotherapies fail. Currently, that space is unexplored. We have to gather much more data before we can make conclusions about those with underlying DNA repair defects who have failed platinum-based chemotherapy or PARP inhibitors.

This is an area of active and important investigation that represents a conundrum for many patients today. I’ve got a patient right now going through this. We’re debating what to do next. I’ve tried to be as honest as I can when I say, “I don’t know what to do, but we’ve got to try something.”

We are in the middle of a revolution, but the parts and pieces are not yet clear. For some, understanding tumor genetics at the current level is helpful. For others, it is perplexing and expensive.

Join us to read this month’s conversations about prostate cancer genomics.

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Join A CAR T-Cell Therapy Trial For Prostate Cancer

Dr. Naomi Haas is the leader of the kidney and prostate cancer programs at the University of Pennsylvania Health System in Philadelphia.

Prostatepedia spoke with her about her Phase I chimeric antigen receptor (CAR) T-cell therapy for prostate cancer clinical trial.

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Dr. Naomi Haas: Patients are interested in approaches that could potentially allow them to live for very extended periods of time without a lot of side effects. The prostate cancer field has evolved very quickly. We have a lot of new agents that we didn’t have even three or four years ago.

One of the things that has come out of the University of Pennsylvania is that Dr. Carl June is doing a lot of CAR T trials in different solid tumors—including prostate cancer.

This particular immunotherapy trial we’re discussing collects patients’ T-cells and exposes them to a virus that has a target in it. We then give these cells back to the patients to train their bodies to attack the cancer.

It’s a very attractive approach. We started developing this clinical trial over five years ago. At the time, a lot of the therapies didn’t include some of these small molecule pill-type therapies that patients could take. We were interested in developing nontoxic approaches for patients that would hopefully incorporate into their immune system and would work for a really long time.

Can you walk us through the details of the trial?

Dr. Haas: Patients first have testing to see if their cancer expresses the same kind of targets that we’re making in the CAR T trial. They have to have a biopsy of their tumor, which shows that their prostate cancer expresses a protein called prostate-specific membrane antigen. PSMA is similar to PSA, but this protein is secreted on the outside of the prostate cancer cells. It’s on the membrane, so it’s much more accessible to treatment. It might bring down cells that a PSA target might not otherwise do.

So, patients first undergo testing of their tumor. If they have at least 10% expression of PSMA, then they’re a candidate for the trial.

They then undergo a process called apheresis: an IV is put in their arm and their blood comes out into a machine. This machine removes some of the T-cells—the immune cells—from their bloodstream, but their blood is at the same time returned to the body. They’re not really losing a lot of blood. We’re just pulling some of the T-cells, the T-lymphocytes, out of their bodies.

Then we infect those T-cells with an inactivated HIV virus. This is the same virus that causes HIV, but we remove the bad stuff so that it can’t cause HIV in patients. We put two targets within this inactivated virus: PSMA and TGF-beta.

TGF-beta is an immune marker present in a lot of the lymphocytes. In prostate cancer, the lymphocytes hang out near the prostate cancer cells, so we felt that if we targeted both we would have a better chance of hitting the tumor with our target and not hitting other parts of the body that we didn’t want to harm.

Once these cells are infected with this CAR T, they are grown in culture. We make volumes of these T-lymphocytes with this antivirus with PSMA and TGF-beta in it.

The process takes about three weeks. Then we give it back to the patients through an intravenous line over about half an hour. It’s just a one-time treatment.

We then follow people very closely over a number of days, weeks, and months. We make important measurements, such as how much the T-cells expanded in the blood. We also do another tumor biopsy to see if the CAR T has reached the tumor.

We follow scans, blood tests, etc. to make sure that: 1) the patients aren’t having side effects; and 2) to see whether or not we can prove that the CAR T has incorporated into their bodies and that it’s doing its job.

We’re in the very early stages of this clinical trial. We’re looking first at a low dose of CAR T and are planning look at higher doses and then multi-doses because we think patients might need more than one dose to offer an effective therapy. We’re also looking at CAR T in combination with immune adjuvants. Sometimes we give a little dose of Cytoxan (cyclophosphamide) or a little dose of fludarabine with CAR T to make the body have an even bigger immune response.

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CAR T-Cell Therapy For Prostate Cancer

Dr. Susan Slovin is a medical oncologist specializing in prostate cancer immunology at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia spoke with her recently about immunotherapy for prostate cancer.

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Dr. Susan Slovin: My career goes back probably 40 years when immunotherapy meant that you tried to devise a variety of different platforms to influence the human immune response so that it recognizes and fights cancer. We didn’t have the same level of sophistication in understanding the inner mechanisms of the immune system we do now, and frankly, in the 1970s, we were just identifying that there were two cells that governed the immune system, B- and T-cells. The world, unfortunately, has become checkpoint-centric much to my dismay. I believe that people think that checkpoint inhibitors are synonymous with immunotherapy. There are other immune treatments that continue to be investigated, but may not be easily exportable into clinical practice due to their uniqueness and complexity in development. This is, in fact, the case with CAR T-cell therapy. CAR T-cells (chimeric antigen receptor T-cells) are another platform whereby we engineer a patient’s immune T-lymphocytes (a white blood cell that is known to fight the cancer cell) to treat their cancer. We’ve been focusing on patients with metastatic prostate cancer to the lymph nodes and/or bone tissue who have failed other therapies but have not had chemotherapy before. They essentially have had multiple hormonal therapies.

We are using the body’s immune system in a different way than checkpoint inhibitors.

The body has two cell types: first, we have B-cells, which produce antibodies. Antibodies are proteins in the blood that fight infection or recognize molecules that don’t belong there. And second, there are T-cells, which are white cells involved in immune surveillance and tumor cell killing. In other words, they scavenge the body looking for molecules that don’t belong. Molecules that don’t belong include foreign cells, bacteria, and viruses. And, remember that cells also go to the bathroom and they leave behind waste products that may be foreign to the immune surveillance cells. These cell products, along with cells that die as a result of radiation or chemotherapy, provide novel antigens or molecules that may never have been seen before by the immune system and may invoke the immune system to respond and protect the body.

The immune system does not react against things that don’t pose threats to it. But the use of CAR cells takes advantage of the fact that T-cells are the largest cell population in the body and that they are the ones involved in effecting an anti-cancer response.

T-cells are part of the CAR therapy approach called adoptive cell transfer. It’s a little different from what’s been done with Provenge (sipuleucel-T), which is, ironically, the first autologous (self-derived) immune cell product used for the treatment of a solid tumor for prostate cancer. What’s ironic about that is that here we are in the world of prostate cancer for which we have an approved immune-based therapy but which appears to be minimally responsive to the more widely and successfully used checkpoint inhibitors.

Unlike Provenge (sipuleucel-T), which stimulates the patient’s dendritic (antigen-presenting) cells, adoptive cell transfer uses only a particular population of the patient’s immune cells to treat their cancer, mainly their T-cells.

CARs are approved in two indications: acute lymphocytic leukemia and lymphoma, but as yet have not been demonstrated to have antitumor efficacy in solid tumors. They are formed by engineering T-cell receptors, which graft a molecule with particular specificity onto an immune effector cell (T-cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T-cell (for example prostate-specific membrane antigen [PSMA]) with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources. The upshot is to be able to develop an “armored CAR,” that allows the T-cell to seek out cells that express that same molecule and therefore will ultimately engage the cancer cell that expresses the molecule and kills it via a variety of mechanisms. These include the recruitment of other cell populations and soluble serum factors such as cytokines. In toto, these cell populations also signal to one another to seek and destroy what may be considered foreign to the body. While there are limitations to the technology, we take the T-cell and change or engineer its receptor to express other molecules that recognize a wide range of proteins on the cancer cell. As such, when the T-cell receptor notices that protein, it will immediately follow the cancer cell and bring with it the remaining part of the T-cell to try to affect the cancer.

You can put anything on the surface of that T-cell, any particular kind of molecule, and use it to identify the cancer cells that harbor that molecule.

In prostate cancer, we have PSMA, a molecule that is overexpressed on the surface of prostate cancer cells as they become more resistant to therapy. Our group has used PSMA as a focal point for CAR therapy. We’ve been learning a lot about how to use these cells. It’s a very costly enterprise, and it has not proven perfect yet in the world of prostate cancer. We were able to complete a 12-patient trial looking at CAR T-cells’ ability to track to cancer cells with PSMA on their surface. We know that these CAR cells can migrate to the cancer cells and persist at the site of disease, but they can be unstable and not proliferate sufficiently to continue to interact with the cancer.

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CAR T-cell Therapy For Prostate Cancer

Dr. Saul Priceman is an assistant research professor in the T-Cell Immunotherapy Program at City of Hope in Duarte, California. His expertise is in T-cell biology and cancer immunotherapy. He’s currently developing chimeric antigen receptor (CAR)-based T-cell immunotherapy primarily for breast, prostate, and pancreatic cancers.

Prostatepedia spoke to him about CAR T-cell therapy for prostate cancer.

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Over the last few decades a paradigm-shifting idea has emerged: from before you’re even born until the day you die, you probably get hundreds of cancers. It’s just that your immune system blocks that cancer from growing so that you don’t ever become symptomatic. The cancer you deal with is the one cancer that gets around your immune system and grows. That idea was intriguing to me. Your immune system plays an essential role in your body’s ability to fight everything. It’s the reason why we can live 100 years without succumbing to a plethora of different things that can attack your body, including cancer.

Would you call cancer in general a failing of the immune system?

Dr. Priceman: Not really. Cancer is really many different things that occur in sequence, or simultaneously, that are likely the root cause. I wouldn’t claim that cancer is one thing. But I certainly think cancer is an immune disorder. In a lot of cancers, including prostate cancer, viruses can play an important role in the initiation of that cancer. Cervical cancer, for example, is nearly 100% virus-mediated. So whether your cancer is virus-mediated or not, the immune system plays an essential role in the initiation and progression of that cancer.

I was interested in that idea, but it seemed as if almost nobody else was really interested in this when I got to UCLA.

I went to a virus gene therapy lab and asked the principal investigator of that lab if I could study the immune system and cancer. She said, “I don’t know anything about that, Saul, but I’ll support whatever you do.” For the next four and a half years, I did just that. Together, we made an impact.

I then went to City of Hope National Medical Center, which was pioneering tumor immunology and immunotherapies. I ended up studying how the immune system affected autoimmune disease, obesity, insulin resistance, and cancer in my postdoctoral work. I did well in that area.

And then I realized T-cells are “it.” If you are going to fight an infection properly, or fight cancer properly, you have to engage the T-cells. T-cells are a specific type of immune cell, that are often called the soldiers of our immune system—the fighters that rid us of infections or cancer. I moved into another group at City of Hope to develop chimeric antigen receptor (CAR) T-cell therapy for cancer. The T-cell receptor is a protein on the T-cell that engages another immune cell, a virally infected cell, or a cancer cell to ask: “Who are you? What are you doing here?” If that other cell is not doing the right thing, the T-cell kills it. That process is messed up in cancer. That group was engineering those T-cells to recognize cancer cells as a threat. I got very interested, and that is what I do now. I develop, with a large group of researchers, CAR T-cell therapy for multiple cancers, including prostate.

Where are we in the development of CAR T-cell therapy for prostate cancer?

Dr. Priceman: CAR T-cells are FDA approved for two diseases, which just happened in the latter part of this year. We have CD19-directed CAR T-cells for a B-cell malignancy, whether that is lymphoma or leukemia. These reengineered T-cells go after cells that express the protein CD19, which is expressed on the vast majority of B-cell leukemias or lymphomas. This therapy is now putting patients that are refractory to multiple lines of other therapies in complete remissions, an almost unheard of feat, and changing the landscape of treatment options for these patients.

At City of Hope, we also have clinical experience treating gliomas or glioblastomas that are aggressive brain cancers with similar CAR T-cells. We locally deliver CAR T-cells to the brain for those patients. We’re first in the world injecting CAR T-cells intraventricularly, which is a specific route of delivery that will bathe the central nervous system with those CAR T-cells, so we can attack multifocal brain disease instead of just one site—but still regionally localized in the brain.

Four years ago, with Prostate Cancer Foundation funding, we started to ask, “Couldn’t we get these same responses in prostate cancer?” They gave us a million dollars and two years to make that a reality. We actually just published a paper in OncoImmunology this month on the development of a prostate cancer-specific CAR T-cell. We are going through the regulatory process now and will hopefully start our clinical trial by mid 2018.

How exactly does the approach differ in prostate cancer?

Dr. Priceman: The target protein is very different. It’s overexpressed in prostate cancer in the majority of patients. One of the benefits of targeting our CAR T-cells to this protein is that it is also expressed in pancreatic, bladder, and other solid cancers. We’re trying it first in prostate cancer, but we also think that we can make an impact in these other diseases eventually. The target is called prostate stem cell antigen, but that is a little misleading because it is expressed in some non-prostate cancers.

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