Dr. Eugene D. Kwon Video (Text Version)
Checkpoint Blockade for Prostate Cancer Immunotherapy
Natasha Kyprianou
From genetics to immunotherapy for prostate cancer it is my pleasure to introduce the next speaker, Dr. Eugene Kwon to talk about immune checkpoint inhibitors. Dr. Kwon is Professor of Urology and Immunology at the Mayo Clinic in Rochester, Minnesota. Dr. Kwon is a prolific physician-scientist with an active research program pursuing the preclinical and clinical use of novel vaccines and antibodies to activate anti-tumoral T-cells in order to induce tumor regression in castration-resistant prostate cancer. With longstanding support by the PCRP, Dr. Kwon’s group was the first to report the potential utility in blocking the first inhibitor of cell immunity for the treatment of prostate cancer. This morning, Dr. Kwon will be discussing his work on immune checkpoint inhibitors in prostate cancer; Dr. Kwon.
Eugene D. Kwon, M.D.; Professor of Urology and Immunology, Mayo Clinic, Rochester
I would like to thank you all for letting me speak today. It is a great honor and I really must say that there are extraordinary people in this room, and they have worked very hard to make massive contributions to the betterment of treatment of prostate cancer. Just like them, I aspire to make similar contributions and hopefully you’ll find this talk interesting. My sense was that when I was invited, that I would be talking about immunotherapy, which is a little bit of a foreign concept and trying to tell you how our research has basically run the full gamut of basic science all the way out to clinical treatment, and I hope that I can make this talk palatable and interesting for all of you.
Before I give my talk I have to provide disclosure. I, myself and the Mayo Clinic have received licensing and royalty payments for B7H1 technologies or B7H technologies that have been basically signed out to various sponsors. Sadly, I also have to report that my net earnings off of these royalties won’t buy any one of you in this room a cup of coffee. So when I was a resident in urology, it became very apparent to me that we had to improve prostate cancer treatment—one of the reasons I felt that it was vital was because I think prostate cancer is a hugely heterogeneous disease; it is very difficult to target. The heterogeneity basically makes it a moving target and undermines strategies with targeted therapy and drug therapies and so forth.
I became very intrigued with immunotherapy and I started reading the literature and I ran across a gentleman named James Allison who I firmly believe is someone that is worthy of receiving the Nobel Prize. Jim Allison had spent his lifetime basically defining how the immune system works and fundamentally he had identified that it takes two signals to turn on a T-cell, which is in green up there. The T-cell receives two signals; one is antigen and one is a costimulatory ligand; those two signals like keys on a nuclear device set off an inflammatory response. It was at that time that I asked him to get involved in prostate cancer research and at our initial encounter I think he was kind of lukewarm about the idea. It was shortly after our meeting that he said he was studying this receptor, CTLA4, which is in red up there and he didn't quite know what it was doing but he said that it might be important and interesting—certainly more interesting than any ideas I had at the time. As his studies ultimately demonstrated, the CTLA4 receptor was the very first receptor ever defined to shut down immune responses, specifically CTLA4 will actually bind up all of the stimulatory molecules, B7.1, B7.2, and instead of activating the immune system, it basically terminates the immune system by either causing the cells to die or become totally unresponsive much like a tenured faculty at a major university institution.
So in layman’s terms and for the purposes of this talk, you have to know that CTLA4 functions like the brakes on the immune system, okay. It causes immune cells to shut down. Based on this, he hypothesized that if you could cap or block that receptor, like throwing a monkey wrench into the brakes, you might be able to cause T-cells to keep going and going (like the energizer bunny) so that they can build an army of T-cells that could swarm upon the target and wipe it out. This army is a-specific, so it is going to recognize variability which is exactly what we want. We want a variable response that can target a variable tumor. I know that there is a lot of confusion out there. These antibodies that we use have been referred to anti-CTLA4 antibodies, MDXO10 and Ipilimumab now. Shortly after these studies were under way, he published a seminal paper in Science 1996 that in vivo blockade of the CTLA4 receptor could be used to treat murine colon cancer in mice. It was shortly thereafter in collaboration with him that I published our papers that suggested using the transgenic adenocarcinoma murine prostate cancer model developed by Norm Greenburg which was the first transgenic mouse to recapitulate cancer that if you treat these mice with this in vivo CTLA4 blockade you could in fact deter or prevent prostate cancer outgrowth in the murine model suggesting utility for treatment of prostate cancer.
Right after that it became really apparent to us that not only do you want to drive the immune response and keep it going and going, going, but you have got to show the immune response where it needs to go. In this study, we demonstrated that if you were to vaccinate the mice first with a vaccine that shows it prostate cancer and then drive the response you could get a blazing response to take down the tumors. More importantly, if we treated normal male mice with this strategy, we could induce autoimmune responses to target normal prostate tissues. This was a seminal paper in the sense that it showed that we could violate the immune barrier between the immune system and the host itself.
I then basically went to the operating table and I was pondering; how are we going to show the immune system where to go using CTLA4 blockade? As I was treating patients I started to realize there may be one standard of care therapy, androgen ablative therapy—could be used to prompt a response specifically androgen ablation, removing of testosterone causes tumors to shrink some. My question was there attendant inflammation within the tumors? I published in the National Academy of Science 2001 that if you take out the prostate after hormone ablation they fill up with T-cells and those T-cells I thought could be used as little pilot lights to get a blazing immune response under the driving forces of CTLA4 blockade or Ipilimumab treatment.
We also published similar findings in mice in the Journal of Immunology. Prompted by this and in another study sponsored by the DOD, we conducted a Phase 2 immunotherapeutic trial to test whether the combination of hormone therapy, plus Ipilimumab or CTLA4 blockade could get you a big response compared to patients that only were treated with hormone therapy alone. This study was conducted over the last 5 or 6 years and I’ll show you some of the results of that. In terms of animation, you know prostate cancer spreads and prospers under the influence of testosterone, and this model shows you a number of tumors. Our hypothesis is that these tumors are very variable and need to be treated, and so what we would do is we would remove hormone or do androgen ablation to cause influx of immune cells to the sites of all the metastases. Then our hypothesis was that if we add Ipilimumab to this treatment we might be able to get an even more robust immune response that would wipe out the tumors causing a very promising partial response or possibly even complete response.
We conducted a study over 4 or 5 years and accrual onto the study was a balance–these are patients with advanced prostate cancer hormone treatment naïve. Unfortunately the end points of this study were entirely based on PSA kinetics, and we were really focused on PSA as a fast readout for the studies and we saw a lot of promising data come out of the study in the sense that it was our impression that the PSA would decline and patients who receive study treatment with androgen ablation and Ipilimumab which the waterfall plots show you, however we were a little disappointed when we showed this to at least one statistician who said wow; you know no big deal. I do not think it is statistically significant. Nevertheless, a number of these patients had interesting contrasting findings. Here is a patient who had androgen ablation alone and what you see there is a cross-section of the bladder with prostate tumor invading right up into the bladder. This is a typical patient on study.
In this slide on your lefthand side, you see the tumor up in the bladder and then after 3 months of hormone therapy you see regression of the tumor but it is not gone. This is a very characteristic response with androgen ablation therapy. In contrast, our patients that received study treatments, many of them were actually, absolutely resolving all of their lesions even within a 3-month time frame. We were a little bit dumbfounded by this finding; we had not seen such robust responses before—occasionally but not consistently. Likewise, patients with widely metastatic disease were able to clear their metastatic lesions even in 3 months of treatment. After a while it became apparent that something was going on and some of our patients were demanding to be taken to the operating room. This gentleman for instance has a tangerine lesion that’s going right up into his bladder, and I do not think I have to point it out for you; I think you can see it. Three months later while he received combined therapy, the tumor had regressed completely to the point that he had no evidence of the disease. He was insistent on having his prostate taken out since we had no other options and we went ahead and removed the prostate. And what we found prior to surgery was that his prostate was packed with tumor; when we took it out we could hardly find tumor. As a matter of fact, we had to step section the prostate to find the tumor. Another consistent finding was huge amounts of vascular sclerosis which was unique and never before described. This is the typical response to hormone therapy alone which shows you that tumors are usually still there after surgery.
Here is another patient, Gleason 10 prostate cancer, completely filling the prostate. He got a combined—this is seminal vesicle invasion; this is inflammation in the prostate. This is what he had; this is all of what he had—less than .1 millimeter left of tumor left in his prostate. After combined therapy it is packed with inflammation, tumor infiltrating lymph sites, seminal vesicles completely normalized, massive vascular sclerosis, massive inflammation by infiltrating lymphocytes. Here is the lymph node with scar tissue where a tumor once was existent.
In summary, we’ve done 18 patients now on this study following either controlled or combined treatment. The yellow ones are the ones that you want to focus your attention on. Some of these patients had PSAs of 740; most of them had T-3, T-4 lesions, and positive ZsM0, or M-positive disease. After treatment, the vast majority of these patients had somewhere between a 70%–100% response to therapy. They had been downstaged by pathologic criteria. Nodal disease had resolved in some; metastases gone. All of these patients are PSA undetectable with up to 5 years follow-up. Just really quickly; there are two Phase 3 studies that are ongoing at this point and you will be hearing about them from Tia Higano and Charlie Drake later on. Both of these are being conducted at our site as well. One is for hormone refractory disease using Ipilimumab and the second is for patients who have failed hormone therapy as well as chemotherapy.
So I’m going to skip the rest of my slides; I’ve gone way over time. I apologize for that. But I have to thank the DOD for its support and I have to thank a number of other people including the NIH, NCI, Dr. Soule from Prostate Cancer Foundation, my colleagues at Mayo Clinic, but most importantly, and I think that is something that is blown over quite a bit, I have to thank Dr. Mishra within the DOD because throughout the year he has been a staunch ally and advocator and supporter of our work and I greatly appreciate it, so thank you.