Conversations With Prostate Cancer Experts

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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.

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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.

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Dr. Tomasz Beer On Immunotherapy

Dr. Tomasz Beer, the Deputy Director of the Oregon Health & Science University Knight Cancer Institute, specializes in prostate cancer oncology. Dr. Beer was selected as one of six top scientists to take part in a research dream team that joins together world-class institutions to study treatments for advanced prostate cancer.

Prostatepedia spoke with him recently about immunotherapy for prostate cancer.

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What is immunotherapy and how is it used in prostate cancer treatment?

Dr. Beer: Our immune systems are capable of controlling, or maybe even eliminating cancer. Immunotherapy provides some sort of treatment or intervention that helps engage the immune system in that task. There are a number of different ways to do that. While we’ve been working on immunotherapy for several decades, it’s still in its infancy. We don’t have a full and complete understanding of how the immune system works and how to manipulate it to our advantage.

We know enough now that cancer treatments that rely on the immune system continue to become a reality for patients and to make a difference.

We’re in that transition period between preliminary and developing opportunities to deliver reliable treatments.

How does it work? In an antigen-specific approach, we develop a vaccine or some other way to activate the immune system against a particular antigen (a protein made by a cancer cell) that is unique or predominant to the cancer.

Another approach is to activate the immune system more generally, and by doing that, hope that the immune system distinguishes between our own antigens and the cancer’s.

These approaches are therapeutic. These are not the sorts of vaccines that we think of in terms of the prevention of infectious diseases, where we vaccinate ourselves when we’re healthy to build up immunity before an infection. Right now, immunotherapy means treatment for an established cancer.

So then these vaccines don’t prevent cancer: this is a type of treatment.

Dr. Beer: Yes. For example, the vaccine against HPV infections is a conventional antiviral vaccine for a viral infection, and because the virus leads to cervical cancer, it’s also a cancer prevention strategy. That is a different way to use the immune system to fight cancer. Immunotherapy is therapeutic cancer vaccination.

Why are some forms of immunotherapy more effective for different kinds of cancer? What is it about prostate cancer that makes it more susceptible to that kind of approach?

Dr. Beer: First, we don’t have a full understanding of these distinctions. Second, just because there are treatments for one disease and not another doesn’t necessarily mean that prostate cancer is more susceptible.

Dendreon, the company that developed the vaccine for prostate cancer, focused on prostate cancer and did not have the resources or bandwidth to try the same thing for other cancers extensively. It’s sort of an accident of history in the case of Provenge (sipuleucel-T).

That particular vaccine targeted a prostate cancer-specific antigen called PAP, so it wouldn’t have worked in its normal form against other cancers. One could take a similar approach with an antigen that was specific to other tumor types, but it just hasn’t happened yet.

With immune checkpoint inhibitors—the most contemporary form of therapy—we think that some cancers are more susceptible because they have more abnormal antigens. The cancers with higher mutational burden seem to respond better to these agents and it’s probably because they’re more different than normal cancers with pure mutations.

There are also other factors. For instance, melanoma or kidney cancers have traditionally been thought of as more susceptible to immune interventions because there are rare patients whose native immune systems were successful against them. But we don’t know if one cancer is more susceptible to immune therapy than another or for what reason. We’re still learning about that.

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Dr. Charles Drake on Immunotherapy For Prostate Cancer

Dr. 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 He frames this month’s Prostatepedia conversations on immunotherapy.

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This is a fascinating time for immunotherapy in prostate cancer.

For the first time, we have a randomized, Phase 3, 800-person trial combining immunotherapy with hormonal therapy. This trial looks at Tecentriq (atezolizumab), a Genentech agent. Patients with metastatic castrate-resistant disease who have progressed on Zytiga (abiraterone) are randomized to Xtandi (enzalutamide) alone versus Xtandi (enzalutamide) plus Tecentriq (atezolizumab). Although there are not a lot of Phase II data supporting this regimen, this is a bold trial concept that could lead to immune checkpoint blockade being FDA-approved for some patients with metastatic castrate-resistant prostate cancer (mCRPC).

On the other hand, in some quarters there is still a lack of enthusiasm for PD-1/PD-L1 blockade in prostate cancer. This lack of enthusiasm is based on older data from the original Opdivo (nivolumab) Phase 1b trial, which included 17 patients with mCRPC. We also didn’t see many objective responses in the anti-CTLA-4 (ipilimumab) Phase 3 trials. This lack of response led to the idea that combination therapies will be needed to go forward. This is not unique to prostate cancer.

Combinations range from immunotherapy-immunotherapy combinations, which are mostly in Phase 1 and 2 trials, to immunotherapy-hormonal therapy combinations, one of which is in Phase 3. In addition, Dr. Doug McNeill has done some nice work combining anti-PD-1 with DNA vaccines. Dr. James Gulley and his colleagues at the National Institute of Health tested similar combinations using anti-CTLA-4 plus ProstVac VF. Other combinations include combined immune checkpoint blockade. Dr. Emmanuel Antonarkis at Johns Hopkins University is leading a trial combining CTLA-4 plus an anti-PD-1 in high-risk (ARV7 splice variant) patients. A second, larger trial of that same combination is being conducted at MD Anderson Cancer Center.

In her conversation, Dr. Naomi Haas talks about the idea of using adoptive T cell therapy, either in the form of chimeric antigen receptor T cells (CAR T-cells) or in the form of adoptive T cell therapy. I think that is a fascinating therapy that hasn’t been brought forward in force in prostate cancer. Dr. Haas and her group launched a trial of PSMAtargeted CAR T-cell. There is a lot of enthusiasm in the field about that trial. It’s worth noting that Dr. Susan Slovin at Memorial Sloan Kettering Cancer Center has also been doing groundbreaking work in adoptive T cell therapy. I think it’s an exciting time for those therapies.

The success of drugs focused on patients with DNA mismatch repair mutations—PARP inhibitors— has led to the idea of combining immunotherapy agents with them. The folks at National Cancer Institute (NCI), particularly Dr. Ravi Madan, have generated fascinating data on those combinations. This work is moving forward at the NCI and in larger trials combining PD-1 blocking drugs with agents like Lynparza (olaparib) and Zejula (niraparib). The early data generated by the NCI group are quite exciting. We’ll see how this shakes out either with other agents or in larger datasets. Overall, it is very interesting.

I’ve been working on immunotherapy for prostate cancer since 2000. We went from irrational optimism about vaccines alone to a bit of depression when some of the large vaccine trials weren’t particularly successful, and as they continue to be unsuccessful as monotherapies. Also, Dr. Tomasz Beer, Susan Slovin, and myself all had cautious optimism about CTLA-4, which very nearly achieved its primary endpoint in a randomized Phase 3 registration trial. That has given way to guarded optimism that we’ll eventually figure this out.

Finally, I’ll add that there are plenty of clinical trial opportunities for prostate cancer patients. But many times, patients jump into the next therapy after one therapy fails, and they do not take some time to carefully consider their clinical trial options. In my experience, prostate cancer patients sometimes seem a bit stunned when they learn that they’re progressing. This is totally understandable. But for many patients, a very reasonable option is to think carefully about which trials might be available to them. One information source is, but simply bringing up clinical trials with their treating oncologist is a great first step.

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Snuffy Myers On Immunotherapy For Prostate Cancer

This month, Prostatepedia is talking about immunotherapy for prostate cancer.

Dr. Charles “Snuffy” Myers offers his thoughts on this month’s conversations.

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Every January we publish an issue on immunotherapy. If you compare our January 2017 issue with this year’s conversations, I am sure the advances in the science behind immunotherapy will excite you. While we only have one FDA-approved immunotherapy called Provenge (sipuleucel-T), the future looks promising.

As Dr. Tomasz Beer points out in his conversation, we’re at an interesting intermediate stage in immunotherapy development. We know that various immunotherapy approaches like vaccines, checkpoint inhibitors, and CAR T-cell treatments can control a variety of cancers, but we don’t yet have an immune-based treatment that has a consistent, major impact on prostate cancer survival or even quality of life.

I’d like to highlight several important themes in this issue. First, evidence continues to suggest a favorable interaction between hormonal therapy and various forms of immunotherapy. Second, there is continued interest in combining immunotherapy with radiation therapy. This offers the hope that immunotherapy might open the door for more effective multimodality treatment.

The emergence of CAR T-cell treatment for leukemia and lymphoma has been very exciting; patients with very advanced disease are entering remission. It will be interesting to see this approach applied to prostate cancer. Also note that major funding for CAR T-cell trials in prostate cancer comes from the Prostate Cancer Foundation (PCF), a nonprofit, and not the United States government. This is a trend I noted last month.

There have been some notable disappointments. The randomized trial testing the Prostvac vaccine failed to meet the requirements for FDA approval. It is still possible that this vaccine might prove valuable in patients with less advanced prostate cancer.

Also, the available checkpoint inhibitors continue to show only modest activity. It may well be that CTLA-4 and PD-L1, the two checkpoint proteins currently targeted, are not the only checkpoint proteins produced by prostate cancer.

For example, earlier this year, investigators from MD Anderson Cancer Center showed that Yervoy (ipilimumab), an agent that targets CTLA-4, triggers production of another checkpoint protein called VISTA. It may well be that prostate cancer can block immune response in a variety of ways and that we need to inactivate each of these defenses.

Even with these difficulties, immunotherapy offers potential benefits that warrant the attention it is receiving.

One of the benefits is that the immune response can evolve over time to match the evolution of the cancer cell population’s resistance. In the laboratory, immunotherapy also offers one of the most robust means of attaining durable and complete remissions.

Join us! Next month we’re talking about what happens when your cancer recurs.


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A New Prostate Cancer Vaccine?

Dr. Charles G. Drake of New York-Presbyterian/ Columbia University Medical Center spoke with Prostatepedia about new prostate cancer vaccines under investigation.

DRAKE charlesNot a member? Join us to read the entire conversation.

Dr. Charles Drake: Hopefully before the end of the year, a trial called PROSPECT will read out. (Though it’s hard to tell nowadays when trials are going to read out because we already have a reasonable number of options: six FDA-approved drugs for men with metastatic castration-resistant disease.) PROSPECT is an international randomized Phase III trial of about 1,200 men that looks at Prostvac, an off-the-shelf PSA-targeted vaccine. The trial’s primary endpoint is overall survival.

Unlike the Provenge (sipuleucel-T) trials, which were sometimes a little complicated to interpret because we had crossover, patients on PROSPECT didn’t crossover. That means that patients on the placebo arm who progressed were not eligible for Prostvac, instead, they went on to standard treatments. The lack of crossover means we expect a fairly clean set of survival data to come out from this large PROSPECT trial. There are a lot of folks in the prostate cancer community looking forward to seeing whether or not PROSPECT will have a survival benefit.

So then we’d have two vaccines for prostate cancer?

Dr. Drake: Provenge (sipuleucel-T) is an active drug with clear utility. The challenge with Provenge (sipuleucel-T) is that patients need to undergo leukapheresis to prepare this personalized vaccine. Prostvac is more like the vaccinia vaccine that was used for smallpox. It will be a bit easier to distribute widely.

Is inconvenience the only factor limiting Provenge (sipuleucel-T) use?

Dr. Drake: The prostate cancer field is like all other fields in that we tend to be trendy at times. When Provenge (sipuleucel-T) was first approved, there was a ton of enthusiasm about it and lots of people were using it. In fact, there was a bit of controversy over whether or not we could make enough of it.

With all the new drugs coming out, Provenge (sipuleucel-T) is probably used less than it once was. But this is something that has been FDA approved and has a clear survival benefit.

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Dr. Drake On Immunotherapy For Prostate Cancer

DRAKE charlesDr. Charles G. Drake recently joined New York-Presbyterian/ Columbia University Medical Center as 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.

Prostatepedia spoke with him about current trends in immunotherapy for prostate cancer

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What are some of the more promising approaches to immunotherapy being investigated now?

Dr. Drake: I’m not 100% sure that everybody in the prostate cancer community is aware of this, but investigators at Merck did what is called a basket trial. They looked at patients with cancers that have a defect in what is called mismatch repair. Cancers that have a defective mismatch repair accumulate many mutations. Those mutations serve as antigens, or targets, for the immune system. It was first shown by Drs. Luis Diaz and Dung Le at Johns Hopkins that in colorectal cancer, where mismatch repair is common, checkpoint blockade with anti-PD-1 is very effective. It turns out that there are mismatch repair patients with every kind of cancer, including prostate cancer.

Based on this large basket trial, the anti-PD-1 antibody Keytruda (pembrolizumab) was recently approved for patients’ cancers that have mismatch repair defects. Across multiple tumor types, there have been really dramatic responses reported in the literature. This means that prostate cancer patients who have mismatch repair defects now have a second immunotherapy option. What percentage of prostate cancer patients have mismatch repair? It’s probably on the lower side, likely in the 3 to 5% range, but since prostate cancer is so common, that is actually a lot of patients.

I think that is fairly exciting and that perhaps the entire community is not completely aware that it is happening. True mismatch repair is rare in prostate cancer, but a significant fraction of patients have other mutations that lead to DNA damage repair defects. Those defects are different and are called DNA damage repair mutations. There have been some studies suggesting that this is actually pretty common in men with metastatic disease—as high as 10 to 20%. Those patients have been shown in a landmark paper by Dr. Johann de Bono published in the New England Journal of Medicine to respond to PARP inhibitors, which are reasonably well-tolerated oral drugs. There are now several ongoing trials testing this.

It is possible that these same patients might also respond to immunotherapy. I was part of a trial that Dr. Julie Graff published last summer that showed that out of the first 10 patients treated with Keytruda (pembrolizumab) who are progressing on Xtandi (enzalutamide), about three had a really beautiful response. Only one had true mismatch repair, but it could be that the other patients have mutations in DNA damage repair. That is important because that would extend the number of patients with prostate cancer who might be eligible for, or likely to respond to, anti-PD-1 or anti-PD-L1 agents.

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