Conversations With Prostate Cancer Experts

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State Prostate Cancer Advocacy Groups Meet

This October 13-15, the 13th Annual Meeting of the National Alliance of State Prostate Cancer Coalitions (NASPCC) met in Washington, DC on Capitol Hill. State prostate cancer organizations, including state coalitions, associations, foundations, and consortia were represented by at least one leader. Invited guests and sponsors also attended.

The first panel on advanced prostate cancer covered new treatments for advanced prostate cancer and appropriate clinical trials. After a detailed Q & A session, a second panel on genomics and genomic testing met. The presentations included information on markers.

Then Dr. James Gulley, lead Prostate Cancer Researcher at Building 10 of NIH spoke about immunotherapy. Dr. Gulley will return at next year’s meeting.

In the third panel of the day, the prostate cancer coalitions of Georgia, Arkansas, New Mexico, South Carolina, and California presented. Mr. Tom Kirk, an invited member of the Executive

Committee of NASPCC and Vice President of the California Prostate Cancer Coalition, moderated the panel. The five state leaders discussed awareness and education programs in their states and expressed a willingness to help other state coalitions as needed.

At lunch, Dr. Michael Zaragoza, President of the Delaware Prostate Cancer Coalition, talked about the current proposed United States Preventive Services Task Force guidelines for PSA testing.

The group later heard Dr. Ashley Ross, a Urologist/Oncologist from Dallas and formerly of Johns Hopkins, discuss important advances in diagnosis and treatment. Dr. Ross’s discussion included genomic testing, early and advanced prostate cancer, and the 2017 results of clinical trials.

Attendees also heard from Mark D. Vieth, Coordinator for the Defense Health Research Consortium (DHRC), who spoke about the urgent need to keep the Congressional Directed Medical Research Program (CDMRP) in place. NASPCC is a signatory of the letter asking that the CDMRP remain in place, and NASPCC joined the DHRC by vote after this year’s Annual Meeting.

The group then heard from panelists who discussed new products and advances benefiting patients with prostate cancer. These included CyberKnife and hydrogel spacer for men undergoing radiation therapy for prostate cancer. A company offering free genetic testing at various centers in the US also spoke.

The group elected its 2017-2018 officers: Merel Nissenberg of California, President; Johnny Payne of South Carolina, Vice-President; Donald Lynam of Kentucky, Treasurer; and Jan Marfyak of New Mexico, Secretary. LaTanya Patton of Missouri is again Director-at-Large. These five officers comprise the Executive Committee, along with Tom Kirk as Invited Member.

The 2017-2018 Board of Directors are the officers named above along with Robert Johnson (Wyoming), Alvin Chin (Virginia), Paul Kradel (West Virginia), Mary Anderson (North Carolina), Dave Hulbert (Minnesota), Ira Baxter (Tennessee), Michael Zaragoza, M.D. (Delaware), and Sanford Jeames (Texas).

Saturday evening NASPCC held a cocktail awards reception. Robert Johnson of Wyoming gave a talk entitled “Why We Are Here,” and then Dave Hulbert of Minnesota talked about his journey as an advanced prostate cancer patient. The group presented two awards: the Georgia Prostate Cancer Coalition won Most Outstanding State Prostate Cancer Coalition of 2017, and Kathy Meade of Virginia received a service award. Guests included the Chief Counsel for Senator Roy Blunt (Missouri) and the Executive Director of the Vietnam Veterans of America. Merel Nissenberg received a surprise crystal award of appreciation.

On the last morning of the meeting, Tom Kirk gave a detailed discussion on “The New Workplan” adopted by the Board on July 18. Andrew Chesler of CancerCare also spoke about a number of emotional and physical issues facing prostate cancer patients and caregivers, which was very helpful in addressing a topic often overlooked at prostate cancer meetings.

The meeting concluded with an open discussion on participating state prostate cancer organizations, co-branding issues, and goals. The group is especially grateful to Tiffany Razzo, who served as staff during the meeting. Next year, the group will meet October 12-14.

Learn more about the NASPCC.


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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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Cancer + The Law

Monica Bryant, a cancer rights attorney, is part of the four-woman team behind Triage Cancer.

Prostatepedia spoke with Ms. Bryant about legal and employer issues facing prostate cancer patients.

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Are there some common legal issues for cancer patients?

Ms. Monica Bryant: Employment issues are an important topic that comes up frequently. We want to empower people to recognize that the law is a tool that they should use for their benefit. We don’t simply advocate that people sue their employers, but we want to get to people before there is an issue.

For example, in the United States, we have a law called the Americans with Disabilities Act (ADA). One of the things that the ADA provides for people with a cancer diagnosis is something called a “reasonable accommodation.” For someone who may be suffering from either long-term or late-term side effects and who wants to work through treatment or return to work after treatment, a reasonable accommodation allows them to get some assistance to remain in the workplace. The average American doesn’t necessarily know about that.

They usually don’t need to know about it, right?

Ms. Bryant: Right. Or they’re into their treatment, they haven’t accessed reasonable accommodations, and then their job performance suffers, so they are let go. We see such a scenario often where people feel they’ve been discriminated against. But when we peel back the layers, it’s not necessarily discrimination, it’s that their job performance has suffered, and they haven’t accessed the benefits that might be available for them.

We want to give people this information so that they can go to their employer empowered and access resources available to them, keep their jobs, and keep being the valued employee they want to be. People shouldn’t suffer as a result of not knowing what’s out there.

What kinds of financial issues do people experience?

Ms. Bryant: That’s an issue across the board. We look at finances in the broadest terms possible because we know that it’s not just about medical bills, even though that is obviously a huge factor.

The issue starts with the health insurance piece. If someone doesn’t have an adequate health insurance plan and their out-of-pocket costs are skyrocketing, that’s going to have a direct impact on their finances. If someone isn’t accessing workplace protection so that they can continue to work, that has a direct impact on finances.

We find that a lot of people think very narrowly about finances, focusing only on financial assistance for copays. While that’s definitely an important part of the conversation, we want people to think more globally. That way, we can avoid some of the pitfalls.

Are finances more of an issue, for example, for people who have prostate cancer? Or are these mostly issues people who aren’t working or who are on fixed incomes face?

Ms. Bryant: We see financial issues from all different types of people, from all walks of life. Even people who would probably describe themselves as middle-class prior to a diagnosis tend to suffer what has now been termed the financial toxicity of a cancer diagnosis.

If someone can’t go to work, works for a small employer, and doesn’t have access to the Family and Medical Leave Act (FMLA), they lose their jobs. Even if they have access to the FMLA, it’s unpaid leave.

For individuals who have lower incomes or who might not have a job that offers health insurance, financial toxicity tends to be more severe. We see this severity in younger adults because they tend to have smaller savings and be less secure in their careers. But it really isn’t limited to any particular segment.

Even if someone is middle class (and I’m not sure how we define that anymore) and has an employer-sponsored health insurance plan, if they’re out of work for more than 12 weeks they could lose their job. Then they have to figure out what to do for health insurance. If they don’t pick an adequate plan, they can exhaust their savings and tap into retirement. Maybe they can’t pay their mortgage. It can snowball very quickly if someone doesn’t understand how to use all of the different parts of the system.

We talk about finances in a global manner because there are so many pieces to the puzzle and each piece is important. Disability insurance is another very important piece. And very few people understand what disability insurance even is and how it can be useful after a diagnosis.

I’m sure most people don’t really understand what it is until they actually need it. And then it’s too late.

Ms. Bryant: Right. And in this country, if you don’t have disability insurance prior to your diagnosis, it can be very challenging to get once you have a preexisting condition.

That makes sense though, doesn’t it?

Ms. Bryant: I would like to see some more options for folks when they’re a number of years out of treatment, especially since so many people worldwide are diagnosed with cancer and since it has become more of a chronic disease. Healthcare industries need to adapt to this change.

That’s especially true with prostate cancer. Most men who have prostate cancer can have it for 10 to 15 years. They die with prostate cancer, rather than of it.

Ms. Bryant: Right. So to deny disability insurance for 15 years to people after they’ve had that diagnosis is extreme.

Are there other issues that come up specifically for prostate cancer patients?

Ms. Bryant: Many people request conversations around intimacy and sexuality. That’s a hot-button topic because it’s challenging to talk about. One of the experts we have in that area says it’s harder for men to talk about those issues than for women to talk about them. We get a lot of traction when we offer content around intimacy and sexuality. Conversations about nutrition and exercise are particularly well received, as well, because people acknowledge that we can improve overall health, but there’s a lot of misinformation out there. The internet is both a wonderful thing and a horrible thing at the same time.

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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.