Advances in Immunotherapy
In this blog PCRI presents an interview from our contributing partner, Prostatepedia.
Prostatepedia spoke with Dr. Charles G. Drake at length about current trends in immunotherapy for prostate cancer. Here is the interview:
Why did you become a doctor?
Dr. Drake: I was originally an engineer. In undergraduate school, I trained as an electrical engineer with a biomedical option. I thought that I would be able to design medical equipment—instrumentation and electronic equipment—that would help people. I wound up getting a masters degree in biomedical engineering. I did research; I was studying magnetic resonance imaging (MRI) and how to make better pulse sequences to measure blood flowing through vessels. But after some time, it became clear that technical innovation was less important to me than understanding the disease in terms of making a difference. I then got my MD and PhD at the University of Colorado. This was a fantastic experience. In the lab, I studied basic immunological and genetic mechanisms in autoimmune disease. In some ways, autoimmune disease, in which the immune system is too strongly activated, is the opposite of cancer, in which the immune system is shut down by tumors. I don’t think I would’ve been happy doing medicine without research or doing research without medicine.
What is your current position at Columbia University and how does the position differ from what you were doing at Johns Hopkins University?
Dr. Drake: This is a harder job. Some things are similar. I have a laboratory that studies the basic mechanisms of the way the immune system responds or doesn’t respond to cancer, particularly focusing on prostate cancer and also other genitourinary cancers like kidney and bladder cancers. That part is fairly similar and is an area that I’m very passionate about. What is different and exciting is that at Columbia, I’ve been tasked with building the genitourinary program. I’m going to hire somewhere between two and four additional physicians focused on genitourinary cancers. Since I’m in charge, I get to shape the program. That is the biggest difference: instead of being a part of a program, I’m lucky to be leading and building a program. My research and laboratory career has been focused on using the immune system against cancer. So, we’re going to build both the clinical trial infrastructure and hire clinicians who are of the same belief that the best way, or the most likely way, to lead to long-term remissions in cancers is with the immune system.
What type of immunotherapy can patients access today?
Dr. Drake: For prostate cancer, the only treatment that is currently available is the vaccine Provenge (sipuleucel-T). It has activity. With all the recent data on new drugs that block immune checkpoints, it’s fallen off the radar a bit, but there are three randomized Phase III trials showing that Provenge (sipuleucel-T) increases survival in men with metastatic castrate-resistant prostate cancer. Another factor contributing to less recognition of Provenge
(sipuleucel-T) is the widespread availability and efficacy of next-generation antiandrogens like Xtandi (enzalutamide) or Zytiga (abiraterone). When it’s used, Provenge (sipuleucel-T) tends to be used earlier in the disease state, either right before or right after second-line antiandrogens.That is what is available now.
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.
Are there any other vaccines being investigated?
Dr. 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.
Are there any promising combinations of immunotherapy with other agents?
Dr. Drake: There are a number of trials looking at combining immunotherapy with other agents. I was involved in a trial at Johns Hopkins University— Dr. Emmanuel Antonarakis is the principal investigator. In this trial, we combined an anti-PD-1 with an anti-CTLA4. In other cancers, this combination doubles response rates and induces more durable responses. The anti-PD-1 and anti-CTLA4 combination is already FDA approved for melanoma. There are Phase III trials that have completed enrollment in lung cancer and kidney cancer; we’re awaiting those results. Emmanuel and I started the first trial in prostate cancer in which we gave that combination to men with high-risk disease—that is men who had a mutation to an androgen receptor. There is now another, larger trial led by my friend Dr. Sumit Subudhi at MD Anderson. They’re going to look at the anti-PD-1 and anti-CTLA4 combination in about 90 prostate cancer patients across various disease states. This will make a really a nice complement to our smaller trial which will finish first. Sumit’s trial will help define which disease state is most appropriate for the anti-PD-1 and anti-CTLA4 combination.
What are the side effects like with this anti-PD-1 and anti-CTLA4 combination?
Dr. Drake: It is a challenging side effect profile. The side effects of the combination of the anti-CTLA4 Yervoy (ipilimumab) plus anti-PD-1 Opdivo
(nivolumab) are usually in the range of 50 to 60% of patients who have Grade 3/4 adverse events. A lot of patients on these trials wind up needing steroids to turn off an autoimmune side effect. The beautiful thing is that the majority of side effects can be controlled with steroids alone. If we can’t control the side effects with steroids, we can use anti-TNF agents like Remicade (infliximab). Early on, there were some treatment-related deaths, but now the side effects are being much better managed. But it’s amazing: when a patient has a response to this combination and you turn off the immune system by treating a side effect with steroids, nearly all of the time, the antitumor immune response remains intact. It’s really fascinating to me you could have an antitumor response that is not sensitive to steroids while the autoimmune side effects go away when you treat the patient with steroids. The point that you raised, though, is that there is a high incidence of side effects with this type of combination. That is absolutely true, but we need to view it in context: these side effects are often quite manageable.Also, clinicians are getting more experienced at managing side effects through the combination’s use in melanoma. If the anti-PD-1 and anti-CTLA4 combination is approved in lung cancer and then in kidney cancer, it will become second nature for oncologists to manage these kinds of side effects.
In other words, it’s a problem, but it’s manageable and we’re working on it?
Dr. Drake: Exactly. I think that we were lucky at Johns Hopkins and even here at Columbia to be able to participate in some of the early trials. We have a bit of a head start managing these side effects, but the average medical oncologist deals with patients without lymphocytes all the time. They also manage patients with severe nausea and vomiting. They could certainly manage autoimmune side effects; they just need to become a little bit more familiar with them.
Is there anything else you’d like patients to know about current trends in immunotherapy?
Dr. Drake: A group of patients generally left out of these immunotherapy trials is men who are earlier in their disease process. That is, men who have a rapidly rising PSA after primary therapy like surgery or radiation. The data suggests very strongly that if a man’s PSA is doubling faster than every 12 months, they’re very likely to have metastases within a year or two if they are not treated. Right now the common treatment is hormonal therapy, but we have some very good data suggesting that we should combine hormonal therapy with immunotherapy. We’re really lucky to have been able to start a series of trials for men with high-risk biochemically recurrent prostate cancer in which we give a short course of hormonal therapy along with immunotherapy. I think that is really an unmet medical need for prostate cancer. We might have a better chance of getting long-term remissions in this disease stage. I know a lot of men in that situation feel bad because there is not that much clinical trial activity for them and not many standard treatments they can have other than hormonal therapy by itself. But we’re cognizant of the problem and are working on it.
What kinds of immunotherapies would you combine with hormonal therapy for these men?
Dr. Drake: We have some unpublished data from a new trial in which immunotherapy and hormonal therapy were given prior to surgery for high-risk patients. Hormonal therapy causes an influx of immune cells into the prostate gland. This is very clear. When the immune cells influx,
they have PD-1 on them. The obvious combination is then hormonal therapy with a short course of anti-PD-1. Quite frankly, I would like to do a trial in which we give a burst of immunotherapy with hormonal therapy, then stop and see if the men can recover their testosterone levels, normal life, and function while not having their PSA and cancer recur. Hopefully, we can get such a trial open. We’ve got some fantastic junior faculty here at Columbia working very hard on it. We have some good corporate collaborators. I hope it will happen within the next year.
What are the obstacles?
Dr. Drake: It’s always a challenge starting a new trial. This is not an industry-sponsored trial. This is an investigator-sponsored trial, and investigator-sponsored trials are always an order of magnitude harder than industry-sponsored trials. You have to write the trial; you have to raise the funding; you have to get corporate sponsorship, at least for the drugs. Of course, you have to go through the regular things like IRB (Institutional Review Board) approval. It’s just a lot harder to do an investigator-initiated trial than one that comes from industry.
There are a lot of different parts to coordinate?
Dr. Drake: Exactly, but in the end hopefully it will be worth it, and will make a difference.
FOR MORE INTERVIEWS WITH PROSTATE CANCER EXPERTS FROM PROSTATEPEDIA, CLICK HERE.
Charles G. Drake, PhD 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, a division of Rivanna Health Publications, has a single mission: to help leading prostate cancer researchers explain their work and its implications to prostate cancer patients, activists, and health care providers. Formerly known as Prostate Forum, Prostatepedia, their monthly periodical, features informal conversations with leading experts.