Conversations With Prostate Cancer Experts

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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.

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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.

(Already a member? You can read all conversations in your copy of April’s Prostatepedia.)

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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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Prostate Cancer Vaccines

Dr. Douglas McNeel is a Professor in the Department of Medicine at the University of Wisconsin-Madison and Director of Solid Tumor Immunology Research within the UW Carbone Cancer Center. Dr. McNeel focuses on prostate immunology and the development of antitumor vaccines as a form of prostate cancer treatment.

Not a member? Join us to read this month’s conversations on immunotherapy for prostate cancer.

Can you give us an overview of vaccines for prostate cancer: which are available now and which are still in development?

Dr. McNeel: If a person has prostate cancer, he usually has surgery or radiation therapy to remove the cancer. These initial therapies cure a majority of patients, but about a third of the time, the disease comes back or resurfaces. We can usually detect the recurrence at a very early stage with a PSA blood test.

Our original thought was that the point of recurrence is the time to intervene, to create a tissue-rejection response.

You can’t really do without a normal kidney. The same is true of the liver.

But you can do fine without a prostate. So if we can create a rejection response to remove any prostate tissue, whether it’s cancer or not, that would be okay.

That was our original thought. The idea with vaccines is to teach the host to generate an immune response that will recognize and destroy cancer cells. But this is a challenge to treat existing tumors with vaccines. With infectious disease vaccines—what we normally think of when we talk about vaccines—we get an immune response that then protects you later on. We call them prophylactic vaccines. But we don’t treat active infections with vaccines. We treat them with therapies that target the bug directly or infuse in an immune system like an adoptive therapy approach.

With cancer, we see the same kinds of hurdles. What we know from animal models is that there are a number of cancer vaccines that can protect animals from cancer, but to get the best response against existing cancers, you have to start when tumors are small and barely detectable. That has been a challenge in pushing those vaccines into human trials.

We’re also learning that when you generate an immune response by means of a vaccination, the cancer can put up a big barrier very quickly to fight against it. Our thought process on vaccines is currently in the midst of changing given that kind of information.

A number of cancer vaccines have been studied over the years. Most of the effort has not produced anything, because we have been looking at vaccines alone, usually in patients with more advanced cancers.

There has been one exception. Provenge (sipuleucel-T), which is a vaccine targeting a protein called prostatic acid phosphatase, was approved in 2010. In this approach, patients have blood removed and their antigen presenting cells are spun out. Then the target of the vaccine, this prostatic acid phosphatase protein fused to an immune-modulating drug, is put together in the lab in the culture dish. The education of the immune system akes place in the lab, if you will. Those cells are then shipped back and infused back into the patient two or three days later. That process is cumbersome, but the approach was shown to be effective.

One large trial led to its FDA-approval. But there were other supportive Phase III trials showing that people who got the vaccine versus those who got a placebo vaccine did better and lived longer. It was a challenge rolling out Provenge (sipuleucel-T) because we don’t see PSA declines with it. We also don’t see changes in the tumors on scans, but we know that men with advanced prostate cancer, in general, live longer if they get that treatment.

Prostvac is an approach that has been in Phase III trials up until recently. Unfortunately, the Phase III trial was deemed to not have met its primary endpoint in September 2017. It did not show that people lived longer. It’s unclear if Prostvac will be developed or not.

Prostvac is a viral vaccine. There is one virus that encodes PSA and then a separate virus. People are immunized with one virus coding the PSA and then boosted with the separate virus. The idea is to use viral vaccines to focus the immune response on the target protein PSA.

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Immunotherapy Combinations

Dr. Ravi Madan, the clinical director of the National Cancer Institute’s Genitourinary Malignancies Branch, focuses on immune-stimulating therapies. In particular, he’s interested in how we can combine these approaches with other therapies to improve patients’ lives.

Prostatepedia spoke with him about which immunotherapy combinations he feels are the most promising.

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(Members can read the conversation in their January issue.)

What kinds of immunotherapy are available now and what is still emerging?

Dr. Madan: There is an FDA-approved therapeutic cancer vaccine called Provenge (sipuleucel-T) that is available in the United States, Europe, and some other parts of the world.

Provenge (sipuleucel-T) is a therapeutic cancer vaccine derived from a patient’s own immune cells. These immune cells are removed from a patient and then exposed to a target protein. Those immune cells are then reinfused back into the patient after that immune-activation phase. The goal is that those activated immune cells will seek out and destroy prostate cancer cells; this has been shown to increase survival in men with advanced prostate cancer, or what we call metastatic, castration-resistant prostate cancer.

Another strategy that is more common throughout the broader medical oncology field is something called immune checkpoint inhibitors. These are approved for and have demonstrated efficacy in many cancers. They help limit regulatory mechanisms that have the potential to turn off immune cells. Sometimes the cancer cells themselves are the ones turning off the immune cells that are trying to recognize and kill them.

On their own, unfortunately these agents have not proven efficacious in prostate cancer. However, several combinations, including some combinations with vaccines, have demonstrated some preliminary evidence of a greater impact than when we just use immune checkpoint inhibitors alone. Several of these combination studies will be very interesting to watch in the near future.

Which combinations do you think appear most promising?

Dr. Madan: There are multiple strategies of interest, but one strategy combines a vaccine with immune checkpoint inhibitors. Our group at the National Cancer Institute, as well as one at the University of Wisconsin, has demonstrated some preliminary evidence that this combination may have an impact. There is also ongoing research looking at combining Xtandi (enzalutamide) with an immune checkpoint inhibitor. In preliminary data, that combination seems to have an impact in a subset of patients.

Why aren’t you looking at Zytiga (abiraterone)? Is there something specific about Xtandi (enzalutamide) that makes it a better combination partner?

Dr. Madan: I’m not aware of any specific studies looking at a combination of Zytiga (abiraterone) and a checkpoint inhibitor, though I wouldn’t be surprised if there are some going on. There is some clinical data that suggests that after treatment with Xtandi (enzalutamide), immune cells may have a higher expression of PD-1, which may create a stronger rationale for the Xtandi (enzalutamide) combination.

In addition to the vaccine combinations, there is a strong rationale to combine immunotherapies with other antiandrogen therapies, including standard androgen deprivation therapy as well as forms of radiation, including definitive radiation.

There are also multiple trials combining immunotherapy with chemotherapy.

Join us to read the rest of our January conversations on immunotherapy for prostate cancer.