 So, for the next hour or so, we're going to talk about a series of topics, immunotherapy, targeted therapy, phase one trials, a panel discussion, and then some additional topics toward the end of the day. We'll have you all out of here promptly by about 2.15 to 2.30. And what I'm going to talk to you about is immune-based therapies. And unlike my colleagues, you'll have to look at me because I have no slides. So I started today talking to you about the transition from the last decade of clinical research and available treatments for kidney cancer to what is really a pivotal time in our kidney cancer history. And as many people think about it, they think that it's something that just began, but in fact it's been decades in the making. So let me, there's four areas that I'd like to talk to you about in the next couple of minutes. The first is something called spontaneous regressions. The second is immune-based therapy with drugs like interleukin-2 and what that's taught us. The third is the role of vaccine therapy. And lastly, we're going to talk about a new class of agents that is not yet commercially available, but that is for kidney cancer, but is reaching the clinic hopefully in the very near future. And I can talk to you a little bit about the pluses and minuses of that. So let's start with spontaneous regressions. So it's been known for decades that kidney cancer is one of the few cancers that when you take out the primary cancer, where there's been spread to other areas, that sometimes in the absence of any systemic treatment, those other areas either decrease in size or disappear. That's what's called a spontaneous regression. It occurs very infrequently, but it does occur. All documented in the literature. So one would ask themselves, what's the mechanism for why that occurs? And the mechanism is thought to be that the primary tumor, the kidney cancer in the kidney, makes molecules that suppress the immune system's ability to manage its cancer. And I think even though that's kind of a 1950s phenomenon in our cancer literature, it has really great importance in 2015, 65 years ago. Because we now know that cancers control our immune response very differently than when we get vaccinated. So for example, many of you got a flu shot this year. It's pretty typical. Everybody, you know, you watch the TV and the TV says, get a flu shot. And you would ask yourselves, well, why do I have cancer and my immune system can't manage my cancer when I get a flu shot? And the flu shot can help me mount a response so that I don't suffer from the flu that comes out this year. And the reason for that is that the cancer is very, very smart. It's not that the flu shots aren't smart. And what it does is it produces an environment around the cells that prevent our immune system from seeing it, reaching it, touching it, and destroying it. And that's what's called immune suppression. And it used to be thought that immune suppression in kidney cancer and other cancers was a result that something happened that happened far away from the cancer cell itself. And the reality is that it's happening right next to the cancer cell, a place called the tumor microenvironment. So the tumor, we always used to think as well, there's these other cells that are inside, and then there's the cancer cell, and it's the cancer cells that drives the conversation. And we now know that it's not just the cancer cell, but all the other cells that are there. And what we're doing fast forward is, well, I'll tell you about how we're manipulating that tumor microenvironment when I talked to you about checkpoint inhibitors. So that was spontaneous regressions. The first hint that kidney cancer might be different. If you said to me, well, Dr. Figlin, that must happen in a lot of cancers. The answer is no, it doesn't. Spontaneous regressions don't happen in very many cancers. And kidney cancer is one of the few and infrequent diseases that it occurs in. So then let's go forward and talk about IL-2 and interferon. So IL-2 is a protein. Some of you may have heard about it. Some of you may have received it. Some of you may have benefited from it. And it is a drug approved in 1992 that took about six years to get approved. So mid to late 80s until 1992. And what IL-2 does is it basically hammers, and I use that word advisedly, it hammers your immune system. It stimulates your immune system in a way that nothing else does. Not vitamins, not certain kinds of green, leafy vegetables, not anything that the pharmacist or the TV tells you are immune stimulants. But it's a drug that basically hammers your immune system. And when you hammer the immune system, one of the things that occurs is you create an environment of cells that then seek out and have the capacity to destroy cancer cell. And in kidney cancer, when you think about kidney cancer now, what is that, eight and 15, 23 years later from its approval, if you asked an audience, whether it's this audience or any audience about who are the multiple decade survivors of kidney cancer, it's patients that received IL-2. So Nancy and I have patients that are 20 plus years free of metastatic cancer from IL-2. The problem with IL-2, unfortunately, is that it's very infrequently works, usually less than 10% of the time, and it requires multiple hospitalizations in the intensive care unit where you get very, very sick. And it's not really been adopted by most physicians around the country, because, one, they don't have the experience, two, the frequency of benefit is low, and that's independent of trying to identify the people that are most likely beneficiaries. So one of the questions that I've spent a significant part of my scientific life is to try and identify who most likely benefits, because boy, if we could identify the people that would benefit, then we could treat just those and not use that treatment for people unlikely to help. And we have an article that just was published that looks at that, but fast forward 23 years and we, although we have tried, we've not been very successful. So the gentleman in the second row asked about chromophobe. We know that it doesn't work in chromophobe. We know that there's certain subpopulations of patients where IL-2 can work, but even so, the success rate is usually less than one in 10. But what it did tell us was that the interaction between the immune system and kidney cancer remains a potential for curative therapy. And remember I used that word earlier. So fast forward to the kind of 2005 to 2012, we're starting to talk about vaccines. What are vaccines? Well, vaccines are no different than the flu shot that you take. The flu shot is an inactivated flu of certain strains that stimulate your immune system to protect you against the virus. We now have at least two large randomized clinical trials in kidney cancer using two different vaccine approaches. Vaccine one is an off-the-shelf vaccine that's combined with a drug that many of you may have received, Sutent, or a drug like Votrient, where the hope is that we stimulate the immune system against things on the surface of the cancer cell, which when combined with Sutent results in improved long-term control of the cancer, that trial has been completed. We're waiting for the results. Results probably won't be known for another 24 months. The second is a little bit different, and that's a trial where the vaccine is actually generated from the patient's own tumor. This is what's called a personalized autologous vaccine, meaning that it doesn't come off the shelf. It comes from you, and we take that tumor and we process it. We extract what are called the proteins on the surface of that cancer. We grow it in the laboratory. We put it on top of your immune system cells called your dendritic cells, and we give them back to you as a vaccine, much like a flu vaccine in combination with Sutent. That trial has now about 300-plus patients on it of the 450 that will be required. It's a trial taking place at 160 places around the world, and we'll hopefully have the results of that by 2016, about a year and a half from now. One can imagine that we are now trying to exploit your immune system on behalf of destroying your cancer. The last area, which is incredibly novel, is the realization, and this was actually first described in kidney cancer mid-2000s, so about 2004, by a group at the Mayo Clinic, Eugene Kwan. What they described was that there are these molecules on the surface of a kidney cancer cell which make the outcome for that patient less well than if the molecules were not on the surface of a kidney cancer cell. And then fast forward about eight years, travel from Rochester, Minnesota, to Baltimore, Maryland at Johns Hopkins, they realized that these molecules called checkpoint inhibitors are molecules that do the following. The cancer cell tells your immune system through something that it makes to block the immune reaction between your cancer and the cancer cell, between the immune system and the cancer cell. So imagine that this is the cancer cell and this is your immune system, there's something in between that despite a strong reaction can never see each other and interact. And that blocker was understood and as most of what happens in the world of oncology, industry gets involved at some point and we developed blockers to the blocker and you do that in the form of an antibody. So what you do is you say to the immune system, I'm going to give you this treatment and what's going to happen is the immune system that is being blocked by the signal between the cancer cell and the immune system is going to be blocked further by this drug that we're going to give you, a so-called checkpoint inhibitor blocker. Lo and behold, you clone it, you make it, you give it to people and there are now two diseases that, well, one and a half, let's say, where this drug has been beneficial, this class of drugs. It's approved in melanoma and it's soon to be approved in lung cancer. And what's amazing about this approach is that it's evident that diseases that are not thought to be immunologically reactive are now becoming responsive to immune manipulation, lung cancer, for example, where you wouldn't have expected that to occur. So we've participated in the kidney cancer trials, those trials have accrued, met all of their goals and we're waiting for those results and we would expect that kidney cancer will be one of the diseases where these checkpoint inhibitor blockers will be approved hopefully in 2015, possibly in the first half of 2016. Now, but we've learned a lot, going back to our IL2 conversation, that only about one and 10 benefit and the same is going to be true for the checkpoint blockers and that is that despite the fact that it's very exciting, it doesn't appear that everyone benefits from these drugs and we think that the benefit usually resides in about 20 to 30 percent of the patients. So again, much like the science that we did over the last couple of decades, it will be what is it about these people and what is it about this disease that allows these immunologic manipulations to work in some people and not in others. The other challenge is that when you turn on an immune system or you block the things that are blocking the interaction, you then are exposed to other immune reactions that might not be okay. You can develop diseases of the thyroid, of the adrenal gland, of the pituitary, of the gastrointestinal tract because when you turn on an immune system, you sometimes don't have complete control over the interaction between the immune system and the cancer cell or the immune system and other parts of our body. So while very exciting, also potentially very challenging with respect to how it's given, how it should be combined with other agents and who are the best people to receive it. So I'll circle back and talk to you about this later when we talk about some of the research that we and others are doing toward the end of today, but I think that my own bias is that the immune approach to kidney cancer, which was quiescent over the last decade, has reblossened and that reblossing of that effort is going to have a profound impact on the kinds of things that we can offer you and patients like you in the future. So I'll take a couple questions because we have a couple minutes and then we'll move on to some other topics, but we'll have a panel discussion later. Any questions? Perfectly clear. Dr. Mr. Kot, you must have a question. Use the microphone. Exactly. Yes. Yes, so the question that's being asked is there are five companies that are now internationally competing for this space. All of them with a little bit of a different approach. And the question is if one doesn't work, might the other one work? And we don't have any evidence that that's true yet. There's no data in the literature that would suggest that if A is ineffective that B can be effective, but we will see those evolve over time probably within this year, but currently there's no evidence that that's true. Following up on the questions about biomarkers from Dr. Lutheringer, are there real good tests to indicate which patients at this point are more likely to respond to some of these checkpoint inhibitors or ways to exclude patients? Right, so the easy answer to that question is there are no good tests to predict who will be a beneficiary and who will not. Those are tests that are being looked at and evaluated, but there is not a blood test, a tissue test, or some other kind of test that can predict how a person will do, although we look continuously.