 So to complete the this morning session, there's a little bit of a change in the in the schedule. Our next talk is actually appropriate going to be our vaccines and novel immunotherapies promising in the treatment of kidney cancer and we're joined by some on to Paul, who's the director of the kidney cancer program at City of Hope Comprehensive Cancer Center. Thanks for coming. Thanks so much, Dr. Figglin. My name is Monty Powell. I'm over at City of Hope and before we begin, I really just wanted to give a huge thank you to Dr. Figglin and Nancy and the KCA for organizing this conference every year. You know, many of us in the audience know Dr. Figglin as a superb clinician and someone who's really brought a number of new therapies and kidney cancer to the home. But what we don't often see in our day to day interactions with him in the clinic is that he's a really outstanding teacher and I give him full acknowledgement for teaching me everything I know about the disease. Hopefully that's a good thing. So I'm actually going to answer the title of my talk in just one slide. So are new immune therapies and vaccines promising? I think the answer to that is certainly yes. But what I'll suggest it's still pretty early. So we're going to go over a couple of clinical trials that are ongoing right now. Some that are evolving here at Cedar Sinai, some at City of Hope, that may ultimately bring an answer to this question more definitively. Dr. Hoffman gave a great outline of the developments that have been made in kidney cancer over the past several decades. We saw the approval of Interleukin-2 back in 1992. But it's really been over the past decade that we've really seen a number of targeted therapies evolve. And as Dr. Hoffman outlined, these are all targeting blood vessel growth and formation by and large in kidney cancer. So I just wanted to very quickly give you a glimpse of the older immunotherapy data. These are the immune-based treatments that were used in years past. Dr. Hoffman had alluded to interferon therapy and I agree with him completely. What we saw with this, I'm just going to highlight a couple of key points that he's mentioned, are that response rates are very low. So we see a small proportion of patients who actually generate a response to interferon therapy. I'll also point out that we actually don't see many durable responses with interferon. This is in contrast to Interleukin-2, which we'll talk about in just a moment. I'll also propose that the median survival, although this was sort of a benchmark for us a decade ago, was unfortunately not very good with interferon therapy. So if a patient was sitting in my clinic a decade ago and asked me, Doc, what are my odds of making it past a year with a diagnosis of kidney cancer? I'd really have to quote to them some pretty disconcerting data in association with this drug. And it really didn't do a whole lot to delay cancer growth. We saw that in terms of a delay in cancer growth, interferon slowed down tumors for a median of around five months or so. And this was actually the benchmark, as I mentioned before, that we've really improved upon with some of the targeted therapies that we had at our disposal now. So you just heard a moment ago from Dr. Hoffman about a clinical trial that compared Sinitinib to interferon therapy. That was a trial that Dr. Figlin actually led. And Sinitinib really trounced interferon therapy in the context of that clinical trial, and it's really moved ahead in terms of our pipeline of agents. Well, what about Interleukin-2? Here, I'll also concede that response rates in broad terms are very low. In terms of the response rate that Dr. Hoffman referred to around 15%, we see that that's typically the case in association with this drug. The rates of durable response, so these are the really meaningful responses that we see in association with the drug. These are even lower. So the way that I typically summarize the data for Interleukin-2 is that if I've got a room full of 100 patients, so we have five rows of 20 patients each year, we're going to have five to seven patients in that room who have a really good long-term, durable response. And in fact, we've got some of those patients sitting here in this room today, which is really outstanding. But the unfortunate reality of Interleukin-2 is we are going to have some patients who die as a consequence of the treatment, and we're also going to have a number of patients who really don't respond to therapy. If I had to summarize the targeted therapies in one slide, this is perhaps how I do it, and this is generally how I would walk my patients through this in the clinic. If we have that same hundred patients sitting within the room, we're going to have 40 patients within that room have a response to therapy. We're going to have another 40 patients in that room have stabilization of their disease with therapy, but we're going to have 20 patients in that room whose disease unfortunately continues to grow. So this might be an overly simplistic way of looking at this particular problem. But what I would also posit is that with the targeted therapies, we don't have those long-term, durable responses by and large. We're starting to see those evolve, but maybe the proportion isn't quite as high as with Interleukin-2 therapy. How do we predict two benefits from Interleukin-2? My personal contention is that with the older immunotherapies, we really don't have a great way of identifying that, and this is going to be a distinction with some of the newer targeted immunotherapies that we have at our disposal. There was a trial called the Select Study. Again, Dr. Figlin was one of the leaders in this trial. They looked at a total of 126 patients, so this was a relatively large effort, and the main aim of this study was to determine whether or not there was anything within a tumor sample, amongst patient characteristics that might predict clinical outcomes. So we could take that big room of patients and really weed out those individuals who might derive particular benefit from Interleukin-2 therapy. But I would suggest that this study was ultimately negative from that standpoint, and still in 2014 we can't predict who these five to seven individuals in the room are going to be. So what's the future of immune-based therapies? And this is really going to be the focus of my talk today. We're going to divide this into two different subjects. The first is the use of program death one inhibitors, or PD1 inhibitors, and this is a very ominous name, but this drug functionally actually works in a way that's very similar to Interleukin-2. We're really trying to stimulate the body's own response against the cancer. Vaccine therapies fall into two categories, and I'll talk about this. The first is autologous vaccines, which actually derive from a patient's own tumor, and the second category is term multi-pepside vaccines. These are vaccines that can actually sit on the shelf in a clinic that we can deliver without actually having the benefit of the patient's tumor to derive the vaccine itself. And again, these agents all harness one particular weapon against cancer, and it's something you're probably going to hear more and more about, is cancer therapies evolve, and that's something called the T cell. So this is the T cell. It's one of the body's immune cells, and it really is responsible for taking on many of the cancer cells that invade patients with cancer. The T cell interacts with something called the antigen-presenting cell, and I really do think that understanding this is essential to figuring out how these PD1 inhibitors work. So when cancer enters into one's body, basically portions of that cancer is shed out into the bloodstream. Those portions of the cancer are displayed on the surface, this green surface here of the antigen-presenting cell, and when the T cell comes into contact with it, at this particular interface, we actually have stimulation of the T cell, and it begins to respond against the body's tumor. This is perhaps a simplified way to look at that interaction, and it explains how some of these PD1 inhibitors work. This is, again, that interface between the T cell and the antigen-presenting cell. We have the factors on this side that are actually stimulating that T cell to generate a response against the cancer. But, you know, as with everything in the body, there are checks and balances. So on the left-hand side of this diagram, what you see are those balances. Essentially, these are proteins that will interact with one another and actually shut down the T cell's response. So what we really want to do with these novel immune-based therapies is in a very targeted fashion shut down this interaction, and that's precisely what we do with the PD1 inhibitors, or the program-death-1 inhibitors. We actually interfere with the interaction between PD1, which is a protein that sits on the surface of the T cell, and PDL1, which sits on the surface of the antigen-presenting cell. So as you look across the internet, clinicaltrials.gov, other references, you're going to hear about a whole host of therapies that actually target PD1 and PDL1, and this is the mechanism on which they're all predicated. And I'm happy to answer questions about that as soon as this presentation is done. So how well do these drugs work? Well, I'm actually going to focus on data for the one agent that perhaps has been tested to the greatest extent in kidney cancer so far, and that's a drug called nivolumab. So this is a PD1 inhibitor, and just to rehash the mechanism of this agent, basically it's blocking that interaction between PD1 and PDL1 by binding to this very specific site at the surface of the T cell. To date, there was a study performed, a big phase one trial, that didn't just include kidney cancer, it also included lung cancer, colorectal cancer, pancreatic cancer, and a whole host of other types. This study actually did include a total of 34 patients with kidney cancer, and what they found pretty remarkably is that at the two year mark, about half of patients were still alive. Now that in and of itself might not seem remarkable, but when you consider how many treatments these patients had had prior to entry in the trial, I think it's truly fascinating. So about half of patients in this study had gotten three or more prior treatments. What I think is also pretty interesting is we're seeing that same phenomenon of the durable response evolves. So we see that amongst these patients, we had 30% who generated a response. Many were the responses very long term. You see here 96 weeks on the x-axis here, so fairly long responses. One thing that also is pretty bewildering to us in the clinical community is that we're actually seeing responses that last well beyond the administration of the drug. So what you see here in the white bubbles is actually when the response was generated with these agents, in particular patients, each one of these lines represents a specific patient. And what you see here is the time for which the response evolves and the treatment has continued. But in the red bars, we're actually seeing responses that last well beyond the treatment has discontinued. So it's almost like being on drug x and having that response last well beyond drug x. And we're seeing that phenomenon more and more with this class of agents. It's truly something to look forward to. Now, I do want to insert one word of caution here. What I've presented to you is data in 34 patients. This was in the confines of a phase one trial. And those of you in the audience that are familiar with clinical trials know that we go through a whole battery of different criteria to facilitate enrollment. By virtue of that, there are sometimes big selection biases and who we pick and don't pick for these clinical trials. So I would suggest that these 34 patients, who again had been through a mean of three or more prior therapies, are probably fairly healthy folks. And they might not represent the norm for kidney cancer. So I'd urge us to interpret this data with caution, but I would say caution is an enthusiasm perhaps. I'll point out that I've been involved with two other studies. This is a phase one trial of a drug called XL184. It's now known as Cabozantinib. And this was a pretty impressive drug in the phase one setting. We treated a total of 25 patients, many of whom were at City of Hope. And this was also a pretty healthy group of folks. They'd already gotten two prior therapies, but nonetheless met all criteria for this trial. And their tumor delay and growth was actually over a year. So in the context of the treatments that we have at our disposal now, that's a pretty impressive bar. I also let us study, and I put this up here really to, again, exert a word of caution in interpreting the PD1 data of a drug called Pizopinib. And Dr. Hoffman alluded to this drug. This is one of the standard of care agents. It's FDA approved. We could deliver it in the first line setting. When I looked at this drug after patients had gotten two prior lines of treatment, we really saw a phenomenal delay in cancer growth of 17 months. And in fact, the majority of patients on this trial are actually still alive today, four years after the trial was conceived. So whenever we really look at clinical trial data, it's important to really take a close look at the patients that were enrolling in those efforts. So how are PD1 inhibitors going to move forward? This is a trial that Dr. Figlin is actually running here at Cedars-Sinai. This is a trial that takes patients with metastatic kidney cancer. They may have received one or two prior anti-angiogenic therapies. Again, these are drugs like Sinitinib or Seraphinib or what have you. And very appropriately, I think it randomizes them to Evarolimus, which is a drug that we might typically prescribe in that setting, or you might actually get the PD1 inhibitor. And this trial is still ongoing. I think enrollment is close to completion right now, but it'll enroll a total of 822 patients. And this trial might actually be the one to get PD1 inhibitors on the market in renal cell carcinoma. So this is definitely a trial whose results I think we're going to look forward to. I also wanted to highlight a different trial that we're running at City of Hope. This is an exciting one. This actually takes three different study arms, and I'm going to spend a little bit of time going through this. We heard from Dr. Hoffman earlier and from Dr. Kim that there are several promising agents already in our pipeline, like Sinitinib and Pizopinib. What if we were to actually combine those with the PD1 inhibitor? That's exactly what we're exploring at City of Hope. So we've got the combination of Sinitinib and Nevolimab, that same PD1 inhibitor I referred to in the previous slide. We're also looking at Pizopinib with Nevolimab. And then what I think is maybe the most intriguing arm of the study, I certainly can't say the best, but perhaps most intriguing, is the combination of Ipilimimab and Nevolimab. Ipilimimab is an immune-based therapy, and if I could go back a couple of slides to the surface of the cancer cell, Ipilimimab actually blocks a very different interaction at that T cell and antigen-prenosetting cell interface, whereas Nevolimab blocks a different set of proteins. So in this clinical trial, what we're actually looking at is this particular combination of drugs. So two immune-based therapies, given to the patient at once, and I think hopefully that'll shed some light on optimal treatment strategies using these immune-based agents. I'm just going to very quickly allude to a trial that's opening shortly at City of Hope. This is another exciting one that's actually going to potentially move PD1 in addition into the frontline setting. And this is for patients who don't have metastatic disease at the moment. What it will do is it will randomize them once they do develop metastatic disease to a PDL1 inhibitor that's being made by the company Genentech. They could receive that drug alone or in combination with bevacizumab, which Dr. Hoffman alluded to correctly as being one of the standards of care for treating kidney cancer, or synitinib, again, a very valid frontline option. So this trial will be opening up within the next three months at City of Hope. We're very excited to have it on board. And hopefully it's one that would move PD1 in addition to the forefront of therapy of renal cell carcinoma. I'm going to also talk about vaccine therapy and, again, we're so fortunate to have Dr. Figlin here who's been really leading the charge in terms of vaccine therapy development for kidney cancer. What I've alluded to on this slide, and this is a relatively busy one, is that in the domain of vaccine therapy for cancer, we've got Provenge, which is approved right now for prostate cancer. But we've got a whole host of other agents, SimiaVax, DCVax, AGSO03, basically alphabet soup of vaccine therapies that are currently in the pipeline for other cancers, including kidney cancer. And my goal today is to very quickly outline two of the agents, two of the vaccine therapies that are currently in the pipeline for kidney cancer. I'm going to first talk about an off-the-shelf vaccine. So recall earlier I talked about two different vaccine types, one that we could administer to the patient without any preparation, something that's essentially standardized across all patients. And then we've got the autologous vaccine, which is really patient-specific. It's derived from the patient's own tumor. This is actually one of those off-the-shelf vaccines called IMA901. It was actually generated through a very complex algorithm. And rather than going through this, what I'll suggest is that they really went through an extensive process to dichotomize to really figure out differences between normal cells and tumor cells. And what they've identified are key protein-based differences. And it's really those proteins that they're targeting through this vaccine. There is a trial that's completed enrollment right now that takes patients with newly diagnosed kidney cancer and randomizes them to get this vaccine with synitinib or synitinib alone. And again, this is the sort of trial that really may push vaccine therapy to the forefront of treatment in kidney cancer. This is a trial that I give Dr. Figlin full credit for. He's been championing this for some time now, and it's actually in the phase three mode of testing, which is incredibly exciting. This is looking at a compound called AGS003. And this is really where we hope most treatments in cancer will go. This is a highly personalized approach. Basically, when one is diagnosed with kidney cancer, they have their tumor removed. The DNA and RNA-based elements, the genetic information within their tumors are actually siphoned out, essentially. And a vaccine is developed by taking that genetic information and actually more or less plugging it in or forcing it into immune-based cells. So this, again, is a very highly personalized approach. And at City of Hope, when Dr. Figlin actually headed our department, he ran this trial looking at 21 patients with metastatic kidney cancer. These patients all received snitinib in combination with the vaccine. And one thing that I'll point out is that these patients, by virtue of having a tumor in their kidney and disease within their lungs and bones and other sites, were what you might call intermediate or poor risk from the get-go. Dr. Hoffman had alluded to some of these risk categories. So the expectations for survival from the get-go were not great. But essentially, what Dr. Figlin's data shows with the combination of the AGS vaccine in combination with snitinib is that patients with poor risk and intermediate risk disease were living five times as long, perhaps, as we might expect. So that's an oversimplification of this diagram. But I do think that that data was incredibly encouraging. And so what Dr. Figlin is leading right now in combination with a surgical colleague from MD Anderson is a phase III clinical trial. And in that study, patients who have, again, disease that's present in the kidney and at metastatic sites, randomized to receive either snitinib or a standard of care treatment like bosopenib. And they'll receive that in combination with the personalized vaccine therapy. So trials like this, I think, may potentially, again, move vaccines to the forefront of treatment in kidney cancer. So I would suggest the response to targeted therapies isn't bad. Recall that, you know, if we have these 100 folks in a room, we're gonna have the 40 who have a response and shrinkage of their disease, the 40 who have stabilization, and the 20 who progress. But what we really wanna do is harness that benefit that we had in the interleukin-2 immunotherapy era and generate some durable responses. But one thing to keep in mind is that these targeted agents are actually immune-based drugs as well. Drugs like snitinib may potentially augment the immune response. And drugs like seraphinib may actually have the opposite effect and inhibit the immune-based response. So as many of these trials manifest, you're gonna see combination of snitinib and pizopinib with the PD-1 inhibitors, with vaccine therapies. And it's gonna be really interesting and important for us to figure out how these treatments all interplay. So again, hopefully with targeted therapy and immune therapy in combination, we'll turn everybody in this room into a durable long-term responder. And that's certainly what I'm hoping for. So in the clinic, a lot of folks ask me, and I'm gonna diverge here for just one moment and ask, what would you do? So this is 2014. We've got seven FDA-approved agents beyond interleukin-2 at our disposal for kidney cancer. When folks ask me about my approach, I typically divide our therapies for kidney cancer into two buckets. We've got our VEGF-directed bucket with seraphinib, snitinib, bevisizumab, ex-sitinib, and pizopinib. These are drugs that many of you in the room have been exposed to. We've got our mTOR inhibitors, everolimus and temserolimus. What I really think we've gotta do is get outside of these buckets. And I always recommend participation in clinical trials. We have a whole variety of clinical trials available at City of Hope. There are different and important trials available here at Cedars-Sinai. Others that Dr. Quinn, for instance, may offer at USC. And this is a very busy diagram, but it shows you the algorithm that I tend to follow when I treat kidney cancer therapy. We have trials that are intended for patients with localized disease. We have trials for patients who, for instance, have one metastasis in the lung that's resected. The goals of those trials is to prevent the risk of recurrence. And we have trials for patients who have metastatic disease who have had one prior line of therapy or two prior lines of therapy or three prior lines of therapy. So by having these various clinical trials at our disposal, I think we really can potentially stay outside of these two buckets and offer our patients with kidney cancer a maximal number of diverse therapeutic options. I'm just gonna spend one moment going over the list of trials that we have available at City of Hope right now just to give you a sense of what those outside of the bucket options are. I've already highlighted this particular trial, which I would offer to patients who have newly diagnosed metastatic kidney cancer. This again takes that PDL1 inhibitor, the novel immunotherapy, and randomizes patients to that or SNITNIP or a combination of drugs. In the second line setting, we're offering a clinical trial looking at that drug XL184, which I'd mentioned had very compelling phase one data. In the third line setting, we're offering two clinical trials, one looking at a stem cell antibody, which I think is really promising, and another looking at a novel immunotherapy called Sonapsisman. This is being developed by a small company down in San Diego. If a patient has had three prior lines of therapy, we've got combinations of the PD1 inhibitor with VEGF-directed treatment, as I alluded to, and if patients have exhausted all of these clinical trials, we yet still have other studies. This is involving a drug that parallels the VEGF signaling axis, but is nonetheless different called AMG386. So again, by staying outside of these buckets, by maximizing the number of treatment options that we have available for kidney cancer, I really think we can improve clinical outcomes. Thank you. We have a few moments for questions, otherwise we'll go to lunch. Any questions? I'm hungry too. Thank you, Monty. So we will have lunch and you'll be able to bring your... Where? Oh, microphone, please. Thank you. Sounded like all of the clinical trials are geared to clear cell. Is that true? Yeah, so a fantastic point. I don't know if we could launch the slides again for just one moment there. If we can't, it's okay. But what I'll point out is that we actually do have a couple of clinical trials that are available for non-clear cell disease as well. Let me actually fast forward to this clinical trial algorithm here. I'm really glad you brought that up because non-clear cell disease is critically important. So non-clear cell, by the way, represents about 20% of kidney cancers. We have papillary kidney cancer, which is about 10 to 15% of all kidney cancer diagnoses and chromophobic type kidney cancer, which is about 5%. These are not insignificant proportions of the population, so we've definitely got to address them. So I'm going to jump forward to that clinical trial algorithm that I showed you earlier. And in this clinical trial algorithm, one thing that I'll point out is that if you have localized kidney cancer, that's been resected, and we want to employ a preventative therapy, we do have a trial called the Everest study. And it's hard to see over here, but I'm happy to go through the particulars with you. And this randomizes patients to everolimus in the setting of that particular stage of disease. In the metastatic setting, several of the trials, and I've really been working towards this over the past couple years, to have trials in my portfolio that do actually address the non-clear cell population. We have this trial of a stem cell antibody called TRC-105 that's led by Dr. Quinn's group at USC, and they actually do permit non-clear cell histologies, including papillary and chromophobes subtypes. Within the Southwest Oncology Group, I'm actually taking the lead on a clinical trial that's going to be looking at about five to six different MET inhibitors. We think that MET is a protein that drives a lot of papillary kidney cancer. So that trial may evolve over the next two to three years or so, and that may be an efficient way of determining what the optimal therapies are for that particular disease. So I'm so glad you brought that up, and I do think non-clear cell disease is critical, and I think that the bottom line is we're definitely focused on that in our clinical research efforts. Thanks. Thank you. So thanks, Monty. So we have lunch outside for everybody. I think that probably the best thing to do is to get your lunch, bring in here, and relax for a few minutes, and we'll reconvene in about 45 minutes with the second half of our presentations.