 Thank you very much for the kind words and for the invitation to really engage with kidney cancer experts. As David said, I have a number of disclosures to make, patents related to the PD-1 field licensed non-exclusively to a number of papers. So immunology has offered hope for curing cancer for the last 100 years, but hasn't delivered until recently. Work stimulation of the immune response can cure cancers and mice, but these haven't before recently translated to standard human therapies. But new strategies are now working. And this change in strategy is to block immuno-inhibitory pathways. And this works in humans. So we know that tumors can express tumor antigens, and that the immune system surveys tumors for tumor antigens and eliminates many early tumors. But tumors develop multiple mechanisms to evade immune responses. And these include PD-1, IDO, TGF, beta. Now I discovered PD-1 and PD-L2, also known as B7H1 by Leiping Chen's group, and B7DC by Drupart Ohl's group, and show that this engages PD-1. When the PD ligands engage PD-1, it results in tyrosine phosphorylation of the cytoplasmic domain of PD-1. This recruits the phosphatase, SHP2, which in turn defosphorylates proximal signaling pathway molecules of the T-cell receptor. This has the effect of reducing T-cell receptor signaling, reducing T-cell cytokine production, reducing T-cell target cell lysis. Now the PD-1 pathway has an important role in the normal immune response. The PD-1 pathway regulates T-cell activation intolerance. It inhibits naive T-cell activation, as Chuck has shown you. It suppresses effector T-cell function. It can also induce T-regs and maintain T-reg function. Now if you block the PD-1 pathway, what you see is that you get increased cytokine production, such as production of interferon gamma, and you also get increased T-cell killing of targets. Now we've recently developed additional new antibodies for immunohistochemistry and have found some energetic pathologists, Sabina, Signoretty, and Scott Rodig, who have really optimized their use. And we've gotten clinical samples from David McDermott and Michael Atkins at the BIDMC. Now this shows that about a third of solid tumors will express PD-1, and they use it to evade immune attack. And here you can see nice PD-1 staining on the surface of the RCC cells. And Sabina has gone on to extend this, and she has shown that RCC metastases can become PD-1 positive. In the top panels, you see that initially the tumor mass doesn't express PD-1, but when it progresses to a metastasis, it does express PD-1. In contrast, there are other tumors which express PD-1 both as a primary and as a metastasis. We've also begun to look at PD-L2 expression, the somewhat underappreciated second ligand for PD-1, and gotten good immunohistochemistry going there. And this shows that PD-L2 can also be expressed in RCC. The top panel shows a tumor expressing both PD-L1 and PD-L2, and the bottom tumor, the bottom panels, a tumor that expresses only PD-L2 and not PD-L1. Now Topalian has published really groundbreaking clinical studies, and indeed the people who've done the RCC component are up on this podium with Chuck Drake and David McDermott. In summary, these studies show a 20 to 50 percent response rate in clinical trials, and effectiveness in multiple tumor types, including melanoma, renal, lung, and others. The responses can be durable, often lasting multiple years, and the drug is well tolerated. There's not the nausea or hair loss associated with chemotherapy. This really has a different mechanism of action, and it has a good safety profile. Undoubtedly, if it makes it to the clinic, there will be a relearning process by physicians to be more aware of the side effects of an immunotherapy drug, which are going to be autoimmunity. And so there's going to be a learning process of learning to clinically translate these drugs. Now we really learned a lot about the PD-1 pathway through studies with Ralphie Ahmed in studies of chronic viral infections. What we found there is that PD-1 was a T-cell activation antigen. In the solid lines, you see the mean fluorescence intensity of PD-1 expression on antigen-specific T-cells. In an acute infection, PD-1 expression goes up, it peaks at about day seven, and then it gradually declines to low levels as an infection is cleared and antigen disappears. In contrast, if it's a chronic immune response, PD-1 expression goes up and activated T-cells, but if the infection isn't cleared and it stays chronic, PD-1 expression on the T-cells goes up a little more and it stays high. Antigen isn't cleared, the T-cells are repetitively stimulated, PD-1 stays high. And these T-cells are exhausted. They don't make cytokines well, they don't kill well. And the importance of this is that tumor infiltrating T-cells or TILs behave like exhausted T-cells. These are studies with Kumar Duruswamy and George Kukos looking at TILs in ovarian cancer. And what you see is that the level of PD-1 expression in the TILs in both CD4 and CD8 is very high. The vast majority of TILs express PD-1. In contrast, cells in the blood express just a low level of PD-1. And these TILs are exhausted. If you, in the middle panel, if you give them antigen, in this case the NYESO tumor antigen, they make just a little cytokine. The cytokines here measured are interferon gamma and TNF alpha. But if you block the PD-1 pathway, you can see in the upper right that you get lots of expression of the cytokines after PD-1 blockade. So TILs are exhausted. Now early on in our studies of the PD-1 pathway, we tighter in the amount of stimulatory CD80 or 86 signals or inhibitory PD-L1 signals. And what we found is that if you put in a PD-L1 signal that you would shift the dose response curve to the right. You would need strong antigens and lots of them to get a good immune response. In contrast, if you gave co-stimulatories signals, you'd shift the dose response curve to the left. You wouldn't need much antigen or a strong antigen to get a response. So basically the immune response sums up or integrates the positive and the negative co-stimulatory signals and decides on the strength of the response. When a normal cell mutates and becomes a tumor cell, it has a number of changes. And it's estimated that 10 to 200 of these are amino acid changes that are potential antigens for T cell recognition. If the tumor cell expresses PD-L1, it can inhibit T cell functions, particularly of exhausted T cells. The other important thing about PD-L1 expression is that a lot of these tumor antigens are weak or mediocre tumor antigens for T cells. And that if you block the PD-1 signal, you may allow the T cell to really recognize and respond to these weak tumor antigens. But T cell exhaustion is more than just PD-1. T cells express, as you've seen, a large number of inhibitory receptors. Including CTLA-4, LAG-3, CD-244, BTLA, CD-160, TIM-3, and others. And these are all potential, druggable targets for tumor immunotherapy. So the future now is to find combination therapies that work even better. Based on a bedrock of PD-1 or CTLA-4 blockade and adding a second target, preferably with a different mechanism of action. So you can envision PD-1 blockade plus CTLA-4 blockade or TIM-3, LAG-3, CD-244, or CD-160. Or PD-1 blockade plus immunostimulators, such as Ox40, CD-137, IL-2, or TLR ligands. PD-1 blockade plus targeted kinase inhibitors like BRAF inhibitors. Or PD-1 blockade plus angiogenesis blockers, radiation, or histone deacetylase inhibitors to target epigenetic changes. Also, if you have PD-1 blockade, you may much more allow tumor vaccines to engage the immune response and lead to a successful outcome. So this gives you some examples of some of these combination blockades here with treatment of CT-26 colon carcinoma in mice. And the treatment agents are basically after you establish the tumor in the mouse are GVACs, which is a GM CSF producing vector. Or antibodies against PD-1, CTLA-4, PD-L1, or PD-L2. And this slide shows the effect of single agents on the growth of the tumor. And basically, PD-1, PD-L1, or CTLA-4 can give you regression of a moderate number of the tumors. In contrast, if you use dual agents, which is PD-1 plus CTLA-4, PD-L1 plus CTLA-4, GVACs plus PD-1, PD-L1, or CTLA-4, you get better responses. You get a higher percentage of tumor regressions. However, to get total cure in this system, you need three agents. You need the GM CSF vaccine and PD-L1 and CTLA-4, or PD-L1, CTLA-4, and GVACs. So the combination immunotherapy is what has the best effect. Now, I wanted to just interject here that for tumor immunotherapy model experiments, we need a mouse with a normal immune response. And there's a real need in the field for a C57 black six mouse RCC tumor model with inactivated VHL to accurately reflect common human tumors. The common RENCA model used has normal VHL. So it really doesn't replicate what you want. So what we've seen is that immunotherapy can give you lasting benefit. IL-2 and CTLA-4, you can see long-term survivors and a moderate percentage. With PD-1, you can see a higher percentage of long-term survivors. In contrast, the targeted therapies give a high percentage of response, but because it's a single target, the tumor can basically evolve, get around the mechanism of action, and then the tumor will develop resistance and the therapy no longer works and the patient has a poor outcome. So what we're looking for is combinations, which will give you a higher percentage of durable long-term responses and longer duration. And I've given you some of the proposed combinations. The field is looking at additional ones. And I think the future of immunotherapy and combination therapies is bright. I'd like to acknowledge all the people on the slide who've contributed to these studies, particularly the pathologists Sabina Signoretti and Scott Rodig, Arlene Sharp, who's really pioneered the in vivo mouse studies of the normal function of the PD-1 pathway, Rafi Ahmed and John Wary for exhausted T-cells, Kumar Duraswamy and George Kukos for some tumor models, David McDermott and Mike Atkins for really pulling me into RCC and getting me interested in applications there. Thank you.