 So, good morning, and it's always a player to be here, so thank you for the kind invitation. So in the next 25 minutes or so, my thought was to share with you what has happened in immunotherapy, why we've done things, what we've done, where we are in the field at this point and share some of the newer things that may be coming down the pipeline. So here's a patient scan orientation. So this is the table that this patient is lying on, and the feet are towards you. So we're looking through the feet up towards the head. So the head is behind the screen, and so this would be a cross section at the level of the kidneys. This is the left kidney, which is the right kidney. So this would be the right side, left side, back, cross. So it presented with abdominal discomfort and had imaging done, and the imaging showed this right-sided kidney tumor. And at that point he underwent an intervention that was in the form of partial nephrectomy. So this is the scan from March of 2014. This is January 2015. What we see now here is a scar where that kidney tumor was. At the time of initial diagnosis, when he had the kidney still in place, the disease kidney, still in place, what we also saw was a mass that was very close to the spine, involving the bones with an expansile region down here, right there, the dark area that you see. He was followed without any other systemic treatment. And by January 2015, that mass in the spine had disappeared and had become kind of a scar tissue. So the only intervention that had happened in between these two images that I show you was taking out the kidney tumor. There was no other systemic treatment that was administered. So how do we explain that? These observations have been there for a long, long time, and the only intervention with surgery and no other systemic intervention led to the thought process that the immune system was doing something that may have been overwhelmed previously and now having taken out the kidney tumor with trillions of cells in it, now we gave the immune system a chance to equalize the balance. Now, what we did not know was how to get the immune system to work on demand. This is what our understanding of the immune response against tumors is. So here's up on the left corner is a tumor cell, and these yellow blobs you see are there, are the tumor-specific or tumor-associated proteins or antigens. Some of these tumor cells will die spontaneously, and when they die, they release these antigens or these proteins from the tumor into the system. Now, these proteins are then taken up by the immune system cells called antigen-presenting cells. They process this inside their body and attach it to our cell histocompatibility molecules. These are the molecules that decide what our tissue group is, and then in conjunction with that are presented on the surface of the antigen-presenting cells or dendritic cells. Once it is presented in this context, that is when the effector arm of the immune system comprises of T lymphocytes in response against tumors. The T cells now are able to recognize this as something non-self, and they start producing various hormones and cytokines and lymphokines to activate the immune response against the tumor. These cytokines or lymphokines are represented here with these green blobs. They activate the T killer cells, and the T killer cells can now get into the tumor and go and kill the tumor cells. That is what our basic understanding of the immune response against tumors was. What was identified as one of these hormones or cytokines was a substance called interleukin-2. This is way back in the 70s that this substance was actually discovered and was noted to be something that was absolutely essential for growing the T lymphocytes in culture. Prior to having known about interleukin-2, we could not grow T lymphocytes in culture. Steve Rosenberg at the NIH started using very high doses of IL-2 or interleukin-2 to induce growth and activation of T cells in people. He showed responses in disease processes that were resistant to chemotherapy. So this included renal cell carcinoma, this included melanomas, and that is how IL-2 got approval for renal cell carcinoma in 1992. As Dr. Bidding showed us, there are multiple other agents that have been approved since. Until 2015, when we saw approval of Nevolumab, I'm just going to talk a little bit about IL-2 and talk about the immune manipulation with Nevo or the anti-PD1 antibody. This is how the IL-2 story unfolded. These are various studies that have been performed. Now you can see that these are not large studies. These are not breast cancer studies. We have thousands of folks involved. These are small studies, and the response rate has varied from about 10% to 15% early on. Later on, it was seen that with certain kinds of histologies or certain kind of pathology, the response rate can be up to about 30%. It's not the response rate that got IL-2 approved. It was essentially this phenomenon where those folks who responded appear to have very durable responses. So resetting of the immune system with IL-2 in some people will result in cures because cure is defined in some ways. You have a response and you're not taking that medicine anymore and the disease is not progressing. So this is a patient who was treated with interleukin-2. This is just a representative CT scan of the chest area. Here's the table, the feet towards you. This is a cross-section of the body at the level of the heart. Anything black is air. This is the right lung, left lung, and what we see are these blobs that are biopsied-proven kidney cancer deposits. And this is in fact dated. This is as of three months back. The scan looks completely clean. And all it took was about four months of treatment initially. For this individual, that actually translated into a cure because now this patient is not on any systemic treatment, any pill or any other intervention that is ongoing. This is a representation of those folks who do get responses, complete responses or even partial responses. So now note out here this is time in months. So we're at about the 10-year mark out here. You know, the higher the graph, more people alive. And farther out the graph, the curve, more people alive. So at 120 months, that's 10 years, these folks who had a complete response still remain in response. That's over 10 years out. Those folks who did not have a complete response that's represented here by this curve out here, these folks also, some of these, still remain in response. Although their scans are not clearly negative. So this is a phenomena that we've seen with immunotherapy. We've not seen with chemotherapy where either you have a response or you don't have a response, we do see scans to be abnormal and yet folks do okay. So the IL-2 was a very crude, in a way, very crude way of getting immune system to respond on demand. Again, here's now our insights into the immune system group. So here's the tumor cell. The tumor cell, some of them die. The tumor antigens are released. They come into the antigen presenting cell. And then they're presented to the T killer cells or T cytotoxic cells as the first step in generation of an immune response against the tumor. In that first step, that is initially modified with an accelerator of the immune system. It's called CD28 that binds to something called B7. So initially what you need is, you need to recognize something as bad guys and then you need to have your killer cells accelerated to take care of them. So that's essentially what is happening. But then nature always has built-in controls. And one of these controls is a breaking molecule or an off switch for the T cell. So here's the activated T cell in red. And then as it gets to, let's get a T cell speedometer. So let's say the T cells are cruising at 50 miles an hour and they see something that is non-self or bad guys. And now once the recognition happens, the CD28 kicks in and accelerates that T cell to 100 miles an hour. But as soon as it gets to 100, the cruise control for the T cell kicks in. And that cruise control is by virtue of an off switch that is called CTLF4 right here. That switches the red activated T cell to an off T cell that is in blue. So the cruise control has now brought this T cell speed back. And what can be done now is to block that off switch and that prevents that T cell from turning off. So the T cell remains active, goes into the tumor and is now going to take care of the tumor cells. Now when it gets into the tumor, there it encounters other forms of suppression. So here's an activated T cell, gets into the tumor. When it gets into the tumor, what happens is there is another breaking switch or off switch that now becomes operant. And this off switch is called PD1. The PD1 doesn't come on by itself like the CTLF4. But the PD1 does get activated when it interacts with its ligands called PDL1 or PDL2 that can be expressed on tumor cells and many other cells. So that results in that red hard activated T cell to be turned off in the tumor. So the tumor cells actually have an inbuilt mechanism to resist the T cells that are trying to kill it. And that now can be blocked with either an agent that blocks the PD1 molecule on the T cell or the PDL1 molecule on the tumor cells. And that results in the T cell not being switched off. It remains turned on and takes care of the tumor. So we talked about CTLF4 blockade and we talked about PD1 blockade. The initial manipulation in renal cell that is reported in a phase 2 study was with nivolumab or NIVO. That is an anti-PD1 antibody. So this is a phase 2 study using multiple levels multiple doses of NIVO for individuals who had pretreated disease. So these were individuals who had up to three lines of treatment. And when they were treated with nivolumab, this is kind of what happened. This is the duration of response. This is the two-year mark. Dr. Bidding showed us a case treated with nivolumab. Each of these bars represents an individual and the red dots represent where they had a response, where a response was documented. The red arrows mark ongoing responses. So these were folks who some of them were very heavily pretreated and yet they had responses and these responses were very durable. So based on this data, the phase 2 studies are generally not practice-changing studies. You have to compare that to an existing standard. Whatever the new entity is, you have to compare that to an existing standard. The existing standard at that point in the second line setting was Evelimus. So the study that was done was compared NIVO with Evelimus. Evelimus is an emptor inhibitor we saw with Dr. Bidding's presentation. And this is what happened in that study. So this is now time in months along the x-axis. This is overall survival probability. Higher the curve, more people alive, farther out the curve, more people alive. And in this study, NIVO showed an improvement in overall survival over Evelimus. So that then got approval for NIVO in the second line setting because these were all folks who had been previously treated. So it was not to say NIVO wouldn't work in the first line but those were the individuals who were included in the study. So that is where FDA approved this agent. It is overall response rate is 25% for NIVO and 5% for Evelimus in the study. So now this is kind of a chart of all the agents that are out there. I was going to talk only about the immunotherapy agents. That's the high-dose interleukin-2 that has been approved in the first line setting for carefully selected individuals. And now NIVO got approved as a second line treatment. So where did we then end up going from there? We started looking at combining immunotherapies with other immunotherapy agents. We also started looking at combining them with the known approved tyrosine kinase inhibitors and with those agents that may actually alter the tumor microenvironment and make it more conducive for the T-cells to work and the immune response to be more robust inside the tumor. One of these is an ID01 inhibitor. I'm just going to show you some data from the combination studies. What else is happening? We need to still figure out how best to dose the... What is the correct dose for these agents? We also need to know how long to use. I was going to ask a bit of a question. This patient has been on for two years. How long are we going to continue treatment with NIVO? We don't know. And then we are looking at several new immune checkpoint inhibitors or immune modulatory molecules. Let me just show you some of these interesting data. Once we knew that we could block the PD1 access and induce responses and we had enough experience with blocking the CTLA4 molecule, we said, can we combine those two? Because they're in different sites in the immune response. The combination study happened. The combination study with NIVO and IPI showed an overall response rate of about 40%. And this was the recent update on where these folks are with the durability of response. So again, this is time in months. The probability of overall survival along the vertical axis. The red line is where half of the individuals are still alive. And the probability with either of these two different doses of IPI and NIVO, either using NIVO at 3 milligram or IPI at 3 milligram, shows that almost three years out, there is still, they have not yet reached that midline. So these are durable responses that are ongoing. And this was a phase one study. So some of these individuals were actually retreated. But the fact is that immunotherapy responses can have this kind of durability. Yes, ma'am. Yes. So in this study, the initial, so they initially got four doses of the combination. And then they continued with monotherapy. So just the NIVO for either two years. In this study, they were continued unless there was evidence of non-response or there was evidence of toxicity. So yes, they are continuing on the NIVO monotherapy. Not the combination. The combination is only the four doses up front. Yeah. So meaning we don't know. Meaning maybe these folks are just getting the NIVO for nothing now. Exactly. We just do not know the answer to that question. So this is data from the same study with different arms of the study. And these arms combined NIVO with either Sunitanib or Zopinib. Those are the two recognized first line agents in real self. The overall response rate for the NIVO plus Sunitanib arm almost 54%. And NIVO plus Zopinib arm 45%. And when we look at their survival curves, this is now because the study was started initially with the TKI and NIVO. They have longer follow up. And so this is the, this is time in months. This is the five year mark. And this is probability of survival. At five years, the NIVO plus Sunitanib arm has not yet reached the median. So this is fairly compelling and interesting data that will need to be obviously reproduced in a larger study. But clearly very, very interesting. Can you go back one slide? The previous one? Yes. Yes, sir. So the, when we use the NIVO with the tyrosine kinase inhibitors with Sunitanib or Pizopinib, the toxicities, the high grade side effects were much more than when it was used with IPI. So for practice changing study and Dr. Bitting showed us some of the data making my job easier. So the practice changing study is a phase three study was looking at the IP plus NIVO rather than NIVO with the tyrosine kinase inhibitor at this point versus standard Sunitanib. This study was recently reported. You already saw this graph. And for those individuals who were intermediate and poor risk, this is time in months. You will note that the follow-up is not as long as we've seen with the previous studies. But the median survival for the combination of immunotherapy is not yet being reached. Interestingly, in this study, those folks who were good risk did better with Sunitanib alone. So that question will still need to be answered. Are we using Sunitanib appropriately or not? What does that mean? What does this study mean? This is the current table of all the stuff that we have. And with the phase three study showing what it did, it is likely that Nevolumab in combination with Epilumab will get approval for first-line treatment. Immunotherapy might move earlier later on in 2018. Now, what I showed you was essentially... So here, let me just clarify what this is. This is the antigen presenting cells that interacts with a whole bunch of these immune off switches and on switches. So on this side are the off switches and on this side are the on switches. And the data that I showed you so far and where we've come in immunotherapy so far in real cell is only being with the PD1 and the CTLF4 molecules. Look at the... And this may not be a complete list at this point. But look at this cartoon and you can see how many other immune checkpoints or switches are still out there that need to be looked at. Some of them are already actively being looked at. We have this RCC fraction study open that is looking at lag 3, dim 3 and cur. These are other immune checkpoints on the T cells. And what this study does is it keeps the nevo as the base and then keeps switching the other immune checkpoint inhibitor. Yes, sir. So where's the tumor on this cartoon? There's no tumor on this cartoon. So these are switches on the T cell. So we're trying to manipulate the T cell. That's where the drug comes in. So the PD1 is manipulated by an anti-PD1 antibody that's nevo. There's another one being looked at in combination with the tyrosine kinase inhibitor. Pembrolizumab or Ketruda in combination with Axetanib is being looked at in a phase 3 study that is ongoing. There has been... Well, some observations that has led to conjecture that the expression of a marker PDL1 that normally switches the PD1 switch may impact outcomes. This data came from the lung cancer trials where it was shown that those tumors that were PDL1 positive and were treated with an anti-PD1 actually did much, much better than those that are PDL1 negative. That data has not clearly been borne out in either kidney cancer or melanoma and a bunch of other disease processes. There appears to be slightly higher response in those tumors that have PDL1 positivity. So in melanoma, for example, if the tumor is PDL1 positive and is treated with immune manipulation, the response is about close to 70% as opposed to PDL1 negative tumors that have a response about 50%. Now, 50% is nothing to walk at in melanoma where traditional response rates used to be 10%. So we really can't use the PDL1 status at this point to not offer somebody that treatment if there's one in two chance of responding. That plus the fact that the PDL1 testing is not yet been standardized on one platform. There are five different tests being used with a cutoff of 1%, 5%, 10%, 50%, and looking at the expression of PDL1 on the T cells versus looking at that in tumors. So I don't know if we really have a true biomarker to predict. And these, we don't need to look on the tumor. These we know exist on the T cells and we're trying to switch them on or off. So this study is already active looking at multiple other immune switches. And just so that you know, it is confusing now what to use. There are about 30 other immune checkpoint inhibitors that are being looked at at this point. Yes, ma'am. So if I understand the question, you know, is if somebody's had a prior IL-2 and now goes on a VEGF therapy, would that impact the outcome? So are we saying that this patient after IL-2 was progressing? Yeah. Okay. So if the patient is not progressing, then why would you start anything? Right. But if the response is continuing, why would you add a VEGF? You would not. It was an observation from a study called the axis study that did actually, so that was a study that looked at exetinib in the phase three setting and allowed prior treatment. So there was a hypothesis generating kind of question that arose from that study because patients could have received IL-2, patients could have received sonetinib and go on the study. Those folks who got IL-2 initially were progressing and then went on to exetinib versus those patients who previously received sonetinib and then went on to exetinib. There was a difference in their outcomes and it appeared that prior exposure to immune manipulation with IL-2 improved outcomes for those folks. So that was not how the study was designed to look at. It's a good question to ask. I think some sort of immune manipulation does impact subsequent treatment, but we need to prove that. So this is kind of where we are and in years to come this talk is going to need more time. I thank you for your attention.