 Great, can you all hear me? Great, thank you very much, Dr. Srinivas, for the introduction. It's a pleasure to speak in front of you all today. We spend a lot of our time speaking with other physicians about how to advance the field. But I think I speak on behalf of all our colleagues when I say that we get the most satisfaction from being with you, the patients. So it is quite an honor to be here with you all today. I also wanted to thank Dr. Diedrich for that great setup for this portion of the talk as well. As Dr. Diedrich was saying, we have made considerable advancements in the field of not only kidney cancer, but also cancer in general over the last several decades. And I actually first wanted to start off with the book recommendation, because I feel that no one actually better chronicles this germany that we've been on over the last several decades better than Siddhartha Mukherjee in his book, The Emperor of All Malades. Many of you may have actually read this book before. But it's a Pulitzer Prize-winning book, which is subtitled A Biography on Cancer. And Mukherjee talks about the evolution that has taken place over the last several decades. And for those of you who may not have the attention span to read a 300-page book, there's actually a PBS series on it, so you can just watch it on TV as I did. And so Mukherjee actually talks about the four pillars of cancer treatment. So I was going to go into those in a little bit more detail. So just to give you a historical perspective of where the field has evolved. So we know back in the day in the 1800s, we actually first started off with surgery, being the first pillar of cancer therapy. So if you ask a surgeon how to take care of a cancer, he or she will say, let's just cut it out. And that actually is very effective in early stage treatments. However, we know that the role of surgery is somewhat limited in advanced cancer. So then in the early 1900s, we actually saw the evolution of what we call radiation therapy. Radiation therapy was invented shortly after we discovered x-rays. And the thought was that x-rays actually cause breaks in the strands of DNA of rapidly replicating cancer cells. So the thought is if we could prevent that from happening, we would prevent cancer cells from replicating. And in the 1900s, it was thought that radiation therapy would be the cure for all cancer treatment. And while that's not quite the case, we do know that it is still very effective. The effectiveness in kidney cancer is still yet to be seen, however. In the 1940s then, we actually saw the introduction of what we call chemo therapy, as you all know today. So something that you may not have known is that chemo therapy actually derived initially from nitrogen mustard gas. That was a tool that was used in World War II as poisonous gas. And when soldiers came back from the war, physicians and scientists actually noticed that their white blood cell counts and the red blood cell counts were severely depressed. So they actually had what we call bone marrow suppression. So a few scientists got together and thought, hey, maybe this is a good idea of a way to treat actually blood cancers. So now it was actually being used in the 1940s as a treatment for leukemia and lymphoma. And then in the last decade, we saw this explosion of what we call targeted therapy, as Dr. Dietrich was just talking about. So targeted therapies is basically an evolution of where we come because our improved understanding of the molecular underpinnings of kidney cancer. So we know, as Dr. Dietrich said, that the protein VEGF, or vascular endothelial growth factor, plays a very important role in kidney cancer. So targeting this pathway and blocking its ability to exist in tumor cells limits the ability of this kidney cancer to grow and divide. Similarly, the mTOR pathway, which is another very important protein and pathway that is involved in the survival of kidney cancer, we know that by blocking this pathway, we have drugs, as Dr. Dietrich had talked about, temserolimus and everolimus that are very effective in kidney cancer. So in the last 10 years, we've seen this explosion of drugs in kidney cancer. So we as oncologists are very optimistic about where the field is going. And now all these drugs are now FDA approved, which is very exciting. So in the last four or five years, however, there's been a lot of buzz in the oncology world, and there's been a fifth pillar that's been added to the cancer treatment paradigm. And you probably guessed that's immunotherapy, as you're probably all well aware. In fact, the director of clinical immunology at Johns Hopkins was quoted as saying, I have such confidence in the potential of immunotherapy that I think the years from 2010 to 2015 will be looked at historically as the time that immunotherapy became the fifth pillar of cancer treatment. So certainly a very exciting time in the field, and I think a lot of people will see this as potentially the golden age of oncology. So how do we define immunotherapy? So I define immunotherapy as harnessing the power of the immune system to fight cancer. And a lot of people will think that this is something that has just began in the last two or three years. But the origins of immunotherapy were actually much farther back than what you may have imagined. It actually dates back to this year in 1891 with this gentleman, Dr. William Coley. So Dr. Coley was a specialist on oncology who specialized in this type of cancer, which is soft tissue sarcoma. And so Dr. Coley actually kept meticulous records of all his patients that he was seeing with sarcoma. And what he noted one day was an outstanding revelation. He actually noticed that patients with sarcoma who were infected with this bacteria streptococcus pylogenies, which manifested as a facial rash or erycypolis, actually lived longer than patients who did not have the infection, which was a very interesting observation at the time. So Dr. Coley did what any illogical person in the 1800s would do, and he started injecting people with syptococcus pylogenies. And what he actually called this, Coley's toxins. And the thought at that time was that maybe these toxins are actually killing the cancer. And lo and behold, he actually saw several responses. So he started injecting patients with bacterial strains, and he started seeing tumors regress or get smaller, which is very interesting. The bad side is that people started dying of syptococcus pylogenies infection, so it wasn't the most effective treatment. But this is kind of the story of how immunotherapy was born. So since that time, now we have a lot more mature data that shows that there is a relationship between the immune system and cancer. And some of the most compelling data comes from patients who have undergone kidney transplant. So when you undergo a kidney transplant, you take certain medications that we call that immunosuppress the body. So there are immunosuppression drugs that keep the immune system at bay so you don't reject your transplanted organ. And so when these patients who have a weak immune system, we know that they have a high susceptibility to developing cancers. So you can see here that the patients with a weak immune system have a 20-fold increase of developing skin cancer, non-Hodgkin's lymphoma, leukemias, ovarian cancer, breast cancer, and it's mattering of the other oncologic problems. So the thought is that if you have a weak immune system, you're more susceptible to getting cancer. So then the thought was that the corollary should also be true. If you have a strong immune system, you should be able to either prevent cancer or eliminate it. So more science came on over the next several years, and one of our first drugs in this modern day of immunotherapy was actually not so modern. It was in the 1970s, and we had a drug called IL-2. So IL-2 works by stimulating T cells or immune cells that you have in your body, causing them to release molecules called cytokines, which wake up a dormant immune system. And this treatment, even in the 1970s, turned out to be extremely effective. So these are patients with metastatic kidney cancer. And as Dr. Dietrich was saying, this is a Kaplan-Meier plot, basically a survival plot. So the higher the line, the better. And you can see here that there were 20 patients out of about 200 who had a complete response, what we call a CR. So they were effectively cured of their disease. So we say one in 10 patients who received this IL-2 therapy was effectively cured. And this is in the advanced setting, so patients with metastatic disease. So this is quite impressive. Here is a CT scan of a patient who has first diagnosed with metastatic kidney cancer to their liver, as you can see by the shaded out region in the liver there. And you can see even 20 years later, this is a scan of a patient who had IL-2 therapy back in the 70s. 20 years later, no evidence of recurrence in the liver. So quite impressive. The problem with IL-2 therapy is that it's extremely toxic, similar to what we were talking about with the bacterial treatments that Dr. Coley was giving patients. These patients often land you in the intensive care unit. So it's very difficult to give patients. And I would say in general, we only give this maybe once or twice a year at Stanford, very, very rarely, because it is so toxic. But this started to give us reason for hope that the field of immunotherapy may be very promising. So as you probably see now, the field of cancer immunotherapy is really a buzz. You've seen this not only in the scientific community, but also in the popular press. So you've seen this on the cover of Newsweek, it's on the cover of Time Magazine, and it was made actually very popular by Jimmy Carter, who was diagnosed with metastatic melanoma, who had disease, both had gone to his liver as well as to his brain. He got a medication with a type of immunotherapy, and he has now rendered disease-free two or three years after starting treatment, which is quite remarkable. So there is a lot of promise in this type of therapy. So November 23, 2015 was a very important day in kidney cancer, because this was the day that the FDA approved its first immunotherapy drug in kidney cancer. And as Dr. Dietrich explained, that was nevolamab or op-divo. And some of you may have seen the commercials on TV with the slogan of a chance to live longer. And that's somewhat debatable, in general, it is a very good drug for kidney cancer, and it is moving the field forward. So how does nevolamab actually work? So I'm gonna take you back to immunology 101, and I'll start off with an example of when you get the cold or the flu. You don't take any medications, you don't even see your doctor most of the time. You take some chicken noodle soup and everything is better within one to two weeks, right? But why is that? So what's actually happening within your body? So your immune system is certainly at work. So your body has these T cells, or these immune cells that are floating around your body, they're essentially your first line of defense system. And you also have what's called these antigen presenting cells. And these antigen presenting cells are looking for foreign particles all throughout the body to bring them to the T cells, to activate the T cells, so that way it's programmed to kill whatever it's looking for. So your body does exactly that with the flu. So your body's able to recognize that there are particles of the flu virus within your body, and you have these dendritic cells or antigen presenting cells bring that particle of the flu to the T cells, activate them, and now you have a robust immune response fighting the flu. So then the next logical question is, why isn't this working cancer? Well, it turns out that cancer is extremely smart. So cancer has developed these escape mechanisms to evade the immune system. So what cancer does is that it holds up this white flag. And this white flag tells the immune system, hey, I'm one of you guys, don't eat me. And so what this white flag called scientifically on tumor cells is called PD-L1. And so this is something that you may have heard of as well on the news as well. So PD-L1 is this white flag that tells the tumor when it engages with an immune cell, don't eat me. And how Novolamab works then is this antibody that blocks this interaction between PD-L1 and PD-1, which is found on the immune cell, and thus effectively lowers that white flag. And when you lower the white flag, you reverse the don't eat me signal to an eat me signal. And then you allow the immune cell to gobble up that tumor cell, that makes sense. So this has been a very effective way of combating kidney cancer and many other cancers in general. So that's how it works in theory, but then does this actually work in humans. So there have been many clinical trials looking at this drug. And the registration trial, which actually showed that there was benefit of Novolamab compared to other targeted therapies, was this trial called the Checkmate 25 trial, that randomized patients who have been previously treated for kidney cancer with different therapies like Su-10 or Presopenib. And these patients were then randomized to either get Novolamab, which is the immunotherapy, or Evrolimus, or Affinitor, as you may know it. And you can see here on this overall survival plot that the patients in the blue arm, which is Novolamab, is significantly better than the patients who got the Affinitor, or the Tyrosine Kinase inhibitor, or the targeted therapy. And you can see here, the p-value, it was, it's a good question, it was significant here actually. The progression-free survival was not seen in the initial trial, but the overall survival was significant. I don't have the p-value here, but it was significant less than .05 though. And if we look at the response rates, we do see that the Novolamab group did have a higher response rate, meaning the patients who either got a complete response, which is very rare to see, only 1% of patients, or at least a partial response, which is more than 20% reduction of their tumor. And we can see that that happened in 25% of patients compared to only 5% of patients with everolimus. While that's great, we would love to see this number improve however. So right now, only one in four patients are responding to Novolamab monotherapy, meaning if you only received that one drug. So what are the side effects of immunotherapy? So the side effects that's noted in this clinical trial are that, well, for one, patients, 20% of patients had what we call a grade three or a grade four side effect. So these are more severe side effects. So at least one side effect that was pretty severe. So that is somewhat toxic, is one in five patients. The most common side effects seen were fatigue, as well as rash, pneumonitis, or inflammation of the lung, which may have been manifest with a cough, an anemia, or lowering of your red blood cell counts. In general, we think of the ituses when we think of the immune-related side effects, because as Dr. Dietrich was saying, most of the side effects are related to what we call autoimmunity, because we're essentially taking the brakes off the immune system. So we're letting the immune system go rampant, and what can happen is that the immune system can start attacking itself. So these are all the different side effects that can happen because of immunotherapy. So if you have your immune system attacking the colon, it's called colitis, and that can show as diarrhea. If you have inflammation of the lung, we call that pneumonitis, and that can present as coughing or shortness of breath. Patients can also get rash, as we talked about, arthritis or pain in the joints, and quite a few other different side effects that you can see here on this chart. So then I want to talk a little bit about how long do you treat for? So this has actually been a little bit controversial because of this concept of what we call pseudo-progression. Pseudo-progression, as opposed to regular disease progression, is an immune-related phenomenon. So what we know in disease progression, in this regular, old-fashioned disease progression, if you put you on a clinical trial and we get a CT scan eight weeks later, if things grow, we assume that's because the tumor itself has grown, so we typically take you off the clinical trial. However, what we've noticed in immunotherapy is that at the eight-week mark, sometimes the tumors look bigger on the scans, but that's not necessarily because of actually tumor growth, it could be because of immune cell infiltration. So you have immune cells infiltrating the tumor so it looks bigger on the CT scan, but if you give it more time and allow the immune system to do its job, you actually see that these tumors start to shrink over time. So this was data that was presented last year that looked at patients who have actually previously progressed on the trial that we just discussed about, the Checkmate 25 trial of patients who got either Everolimus or patients who got Nevolamab, and these patients were actually continued on treatment despite progression. And this is what we call a waterfall plot. So in 150 patients, they actually treated beyond progression and here you can see each of these lines represents a new patient. If the bar goes up, that means their tumor got bigger. If the bar goes down, that means their tumor got smaller. And what you can see is patients who have already shown progression on a CT scan, if you get a CT scan at least eight weeks, if not later, what you can see is that 20% of these patients actually have a response of greater than 30% reduction in their tumors. So nowadays we say that if we can treat for longer, the better. So in general, we try to treat for six months as long as you're tolerating the side effects okay because there's a chance that you could respond later even though your initial scan showed growth. So then the question becomes where does the field go from here? How do we improve upon that 25% response rate? Well so I'll go back to this slide and I'll say that remember when I talked about cancer waving that white flag, well it turns out that it's a lot more complicated than that. There are multiple white flags unfortunately. So the thought is that if we use combinations of different mechanisms of how the tumors evade the immune system, potentially we can get a more robust response. So the field right now is going towards what we call combination trials. So if one is good, is two better? That's the big question that we're answering right now. So Stanford was actually involved in a clinical trial using two immunotherapy agents called one is nevolumab and the other one is called epilumamab. And these drugs work by blocking two different immune pathways that are essentially releasing the brakes off the immune system in two different mechanisms. So we know that the CTLA pathway and the PD1 pathway are both pathways that tumors use to evade the immune system. So we're actually now using drugs to affect both pathways. So this was done in the checkmate 214 trial. So in this trial patients, these are treatment naive patients meaning that they've never seen any other type of treatment for their advanced kidney cancer. And they were stratified by risk and Dr. Gidrick had previously talked about good risk versus poor risk. And essentially this is the risk stratification is based on a series of both clinical parameters as well as laboratory parameters looking at things like your hemoglobin, your calcium levels, your LDH, which is a marker of inflammation in the body. And then they also look to see how long you've been off, you've had to, the time that it took you to start treatment as well as your performance status, meaning how robust you are and how well you're feeling at the time that you're starting treatment. So patients in this trial were actually randomized to two different arms. The first arm received combination immunotherapy with the two drugs that we talked about, nivolumab and ipulumumab. The RMB received a suitent alone. And you can see here, and this is actually hot off the press. This is actually not even published. This is a picture off of a Twitter slide that I saw. So, and it shows that the overall response rate was quite impressive in the intermediate and poor risk patients. And that's important to know because this was not seen in the good risk patients. So the intermediate and poor risk patients, you can see that there was a overall response rate of 42% in the combination arm, versus 27% in the targeted therapy alone arm. And you can see here that there was a 9% complete response rate, almost 10% of patients were having complete responses to the combination immunotherapy treatments, which is quite impressive. And here is the preliminary overall survival curve, which has also been shown to be statistically significant. And it shows that there is a significant improvement in overall survival with the two drugs as opposed to the one drug. And importantly, the two immunotherapy drugs. So as Dr. Dijik was saying, this trial was actually halted early because it was shown that there was a significant improvement on one arm over the other. So they stopped the trial saying that everyone should potentially be getting this treatment. So this may be the new way going forward, potentially in the next several years for this treatment of newly diagnosed metastatic kidney cancer. I will say that these drugs can be, that the toxicity was essentially combinatorial in terms of the side effects that each of these drugs actually delivered. So that's one thing to consider. We don't have all the data. I didn't have all the data in front of me to present to you some of the side effect profiles, but we know that the addition of two drugs can be very, very toxic though as well. So something to watch out for when that data actually gets released. So I wanna talk a little bit about immunotherapy trials here at Stanford. So we know that there's a lot of different ways that we can actually modulate the immune system. We can augment it either by inhibiting an inhibitor, meaning that some of these checkpoints that we talked about, the PD1, CTLA4, we can effectively take the breaks off their immune system to allow the immune system to be more effective. Or the converse is on the right side or the left side of your slide, that you can see that these are all activating receptors. So these actually boost the immune system. So we have a trial now that takes advantage of two of these combinations, the PD1. So we're taking the breaks off the immune system and also using a antibody against CD27, which it works as an agonist and activating the immune system on the other side of it. So we have one that's gonna take off the breaks off the immune system and one that's gonna activate the immune system. And this is a trial of two drugs called, with nivolumab, with a drug called varlumumab, which is an anti-CD27 molecule. And what we know is that in mice, this is actually very effective. These are survival plots in mice and we can do a great job curing mice with a combination of these two different immunotherapies. Now the question is, how are we doing in humans? And this is evolving and we still don't have a whole lot of data yet because it is a phase one, phase two trial. So we're still very early in the clinical trial, but they have published a little bit of evidence that shows that this may be effective. So this is a patient who had metastatic kidney cancer, who's had prior lines of treatment. And you can see that even after one dose of varlumumab, you start to see a small regression of one of the patient's lung nodules. So of course you have to take this with a grain of salt because this is only one patient, but the data is starting to come out to see if this is gonna be more effective. So part of moving the field forward here at Stanford is that we try to get patients on clinical trials so we can see if these drugs are indeed effective because the science is in general very promising. We also have clinical trials that are based on recent data that show that the adenosine pathway is yet another way that tumors evade the immune system. And this likely represents a mechanism of resistance for PD1 therapy. So when drugs like nivolumab are no longer effective, the question is why aren't they effective? And it's probably because these tumors develop secondary mechanisms to evade the immune system. And one of these is the adenosine pathway. So adenosine is actually secreted by these small molecules on tumors called CD73. And when adenosine binds to an immune cell, the T cell at the A2A receptor, it essentially renders the immune cell ineffective. So it's very similar to that checkpoint inhibitor that I talked about earlier. And what we know is that we're now working with a company called Corvus Pharmaceuticals which has built a small molecule to block that receptor that I talked about, the A2A receptor, essentially denying the ability for adenosine to interact with the T cell and therefore leaving it effective and able to kill cancer. So the data still is very naive and we're still getting more and more data is still in the phase one phase right now. But we know that in kidney cancer, it looks relatively promising. So we see that in small numbers, and that's the caveat here, that 60% of patients responded when they were given this drug alone and 100% of patients responded when they got the drug plus another immunotherapy called Atizaluzumab, which is another PDL1 inhibitor. But if you'll note there that there are only 10 patients there. So it's very, very early to say if there's really any signal or not. Dr. Fan has actually started another trial looking at what we call a Glutaminase inhibitor. So Glutaminase inhibitors work by targeting the metabolic pathway of these cancers. And this is actually an interest that many patients come to us with because there's a lot of these popular press information out there about the way sugar affects cancer metabolism. Well, this is actually a Glutaminase inhibitor which inhibits glutamine, which is a sugar metabolite, from getting into the cell. And essentially, this drug is starving the cancer cell and it's being used in combination with immunotherapy to be a potential another promising target for kidney cancer. And finally, I just wanted to speak about kind of where the field is going in general. So those are some of the clinical trials that we have at Stanford. But in general, in the entire field of immuno-oncology right now, a lot of the therapy is going towards combined trials and not just necessarily to immunotherapy drugs, but a lot of combination trials looking at the use of immunotherapy plus other standard treatments, such as the targeted therapy that we talked about. So if you'll see here, these are all very large phase three trials that are undergoing right now, looking at, many of them are looking at immunotherapy, such as Avilumab or Pembroluzumab, in combination with a targeted agent like Sutent or Exitinib. And I think in general, we feel that this may be the way going forward, is that they'll probably have some combination is which treatment will eventually win out. So just to conclude here, we made enormous progress for advanced kidney cancer in the last decades. We have a number of new treatments that are now FDA approved. Cancer and the immune system have a very close relationship, as you have seen through the data. Immunotherapy, such as checkpoint inhibitors, are promising in a subset of patients. And the next steps include combination trials, vaccine studies, and biomarkers to predict who will respond to treatment, which is something that Dr. Fan will be talking about here soon. Thank you all. Any questions? Yes, go ahead. I have a question about something you talked about at the beginning about testing for a weak immune system. Two-part question, how do you test for it? And number two, is it a genetic kind of thing that children should or adult children or some should be tested if they find that we have one? It's a good question. So the slide that I showed earlier wasn't necessarily testing patients randomly for a weak immune system. We were actually inducing in a weak immune system on them because they had a kidney transplant. So what we do is we give them drugs like steroids, for instance, that weaken the immune system so that their body doesn't reject the donated organ. So we were actually giving them a weak immune system. In general, I would say that it's a good question about testing patients' immune system. The biomarker that we look right now to see if tumors are amenable to what we call immunotherapy is a marker called PDL1. And I would say that right now it's prognostic, meaning that we could tell if you're going to do well or not in general with kidney cancer. But we can't predict whether you're going to respond to treatment that hasn't correlated to treatment responses yet. Can you tell the difference whether it's pseudo-progression or it is a real progression? Yeah, it's a terrific question. The question is how do you know if this is truly pseudo-progression or real progression? And I think right now there's, technically there's two ways. One way is that you can technically, if you had a strong suspicion, biopsies the tumor. And if you get back a bunch of inflammatory cells, that may be one way to answer it. Oftentimes we do this clinically though. What we do is we get another scan, potentially four to eight weeks later, to see if there's regression of that tumor. If the tumor continues to grow, we assume that it's real tumor growth. Yeah, it's a great question. Yeah, it's a great question. So the question is about CAR T therapy. So CAR T therapy is chimeric antigen receptor T cells. And what we do is actually is pretty interesting. So this therapy works by taking your white blood cells and extracting them from your body through a process called leukophoresis. And then we take those cells and transfect them with a virus that is able to what we call up-regulate a receptor or a target that hones in on a certain cancer target that you have an interest in. So for instance, in prostate cancer, it can be a PSA. In lymphoma, it can be a target called CD19. The question is how to do this effectively in kidney cancer? And which receptor would you actually want on to serve as a target for kidney cancer? So this has actually been looked at and they have done preclinical models of CAR T cells looking at CA9, which is a target found on kidney cancer. Well, I have to say that they haven't seen any responses or it hasn't been as quite as effective yet in kidney cancer even in the preclinical models. So it's still at the very early stages for shallow tumors in general. It is FDA-approved now in leukemia and a certain type of leukemia. And it looks very promising in certain types of lymphoma. And there was recent data showing that it can be promising even in glioblastoma and multiforme, a type of brain cancer. But in general, I think the field of CAR T cell for solid cancers is probably still a couple of years away, at least a few years away. Okay, thank you so much, Sumit.