 Okay, well, thank you very much for inviting me. I want to thank the organizers here at NYU and the Kidney Cancer Association. And I would like to just say that some of the things that Dr. Alter mentioned in terms of counseling patients are really the bottom line, which is what I always say to people is the name of the game is staying in the game. And Sarah and Paula are examples of that. And some of you are, I know. And what we've learned over the years is that we can find new treatments and new pathways and that's what we're also trying to do with some of the data that you've seen. And I'm going to just talk a little bit about, which way am I going? Those are my disclosures. Okay, there we go. Why immunotherapy? So we're going to talk a bit about why immunotherapy is even a consideration for kidney cancer. Talk about the older immunotherapies, although Dr. Alter gave you a good introduction to that, and then some of the clinical trials that are coming up in the near future. So why do we think about immunotherapy? Well, that's always been the holy grail of cancer treatment, get the body to get rid of this foreign whatever. But the problem is that cancer is us. It's a little bit different. It's a little bit manipulated or mutated, but it comes from our own body. So we have to try to figure out what about the tumor is different and how we can go after it. And that's been the goal of immune therapy. But the reason kidney cancer has always been a target for that is because there's often a long hiatus. People will have a kidney removed and five or ten years later something will show up and you say, what the heck, you know, it's doing again. So what kept it in check for all of that period of time? We also know, speaking of doing surgery in the setting of metastatic disease, it's rare, but we've all seen it, that somebody may come to you with small lung nodules and a kidney tumor and the kidney tumor is removed and then you do another scan before starting treatment. And lo and behold, all of the lung nodules are gone. And what did that? What was that about the primary tumor that was driving the metastatic disease? Was it a growth factor produced by the tumor or did the immune system go after those tumors once there wasn't such a bulky burden of cancer? We don't know the answers to those questions, but those are the intriguing observations that have led us to encourage immunotherapy as a potential therapy for kidney cancer. And as Dr. Alter showed you in his remarks, there is demonstrated responsiveness to interferon, which I'm not going to spend a lot of time on, so I'm grateful that he did. And interleukin-2, both in the laboratory, which is in vitro and in animal models and in people. So who are candidates for immunotherapy? For over the years using interferon and interleukin-2, we've said, you know, we've kind of learned that, as Sarah even commented on and Paula, clear cell seems to be the type of renal cell that responds the best to interleukin-2 and interferon. That's what I say so far. But the checkpoint inhibitors that were briefly mentioned may in fact have a broader spectrum. So think about it this way, interleukin-2 and interferon are substances your body makes normally in small amounts. And what we're doing is giving you super physiologic amounts and we're stepping on the gas. We're pushing the immune system to go after the tumor cells. We're getting cells that are in your body that normally have a very short activation period to stay activated and go after those tumors. Then we're taking these newer drugs, the checkpoint inhibitors, they take the break off. So what we're doing is stepping on the gas and taking the break off. And Paula said that's how she drives anyway with both feet. I don't know, guys. But at any rate, that's the concept of looking at those two things together. And there are the beginnings of some combined clinical trials coming up. So, why is IL-2 still in the picture? Because of what Dr. Alter mentioned, there are durable, complete responders. There are people that have been treated 20 years ago, had a complete response, and have no residual disease in 20 years. There are people who have gotten that disease, had a shrinkage, and then it stayed stable. We don't even know what we see on the CAT scan as active disease. That happens as well. So it's that hope for that complete or durable response that keeps this drug out there and keeps people going through a fairly rigorous treatment, but a short-lived treatment. So what we learned over time was that with clear cell overall, there's about a 20% response rate. The original papers said 15, now it's up to 20. Most recent study we did was 25%. Clear cell with favorable features, which means a very pure clear cell histology, which, by the way, reflects a molecular profile, which will be talked about in the subsequent presentation. The response rate went up to 40%. Now, this is retrospective data. This is looking back. So it may or may not be quite these numbers, but we do know that the histologic subtype and or its molecular profile make a difference in responsiveness, at least to interleukin-2 immunotherapy. Okay, so as was mentioned, it's a growth factor for T cells, which are the killer cells that are activated to go after tumors. It expands these populations of killer cells, and then we keep stimulating them over the course of the treatment for those five days so that they go to the tumor, they infiltrate the tumor. And even after we stop the treatment, those cells are working in the body, because they're alive, they're part of the body's activity. There also are secondary cytokines that are produced that are inflammatory, that are interleukin-1 tumor necrosis factor, gamined or furon. We still don't really know how well they play into what's happening with the treatment. But in the laboratory, more than 90% of tumor cells are killed. In humans, when we give the drug, it's about 20 to 30% of the patients have major responses. So we really are still trying to figure out who and why. Okay, so this was the original data that led to the FDA approval more than 20 years ago, and at that time there was a 15% response rate. But the key was the durable responses, and I'll show you that data. This was a study done at the National Cancer Institute by Jim Yang and his colleagues years ago, and it used three different doses of interleukin-2. It used high dose, which is the inpatient every eight hour treatment. It used a log less of the drug, which we call moderate dose. So it's, again, that every eight hours. Again, five days on, nine days off, five days on. And then a sub-Q regimen that's been used as well. And what we saw was that with the two lower doses, if you look at the bottom column, that's the three-arm study, the two lower doses, the response rate was about half of the high dose. And that, you know, that told us that the high dose was really the most active. But the other part to say that we actually, with our cytokine working group, did a study of the lower dose intravenous. And for people that have medical problems like heart disease or pulmonary disease or kidney problems, they can tolerate that lower dose. And in fact, they can get responses. So there's a trade-off in terms of the overall response rate, but it's not negligible. And for some people, it's the answer. And what you see here, those numbers across the top with all the pluses, that's how long those responses have lasted. And this is an old slide. But the point is, is there are people that are out more than a decade with responses that have lasted after that one cycle of treatment. So that's the carrot for immunotherapy. Okay, so we did a trial called the select trial where we were trying to figure out who are the responders. We still haven't teased out all of the data. But clearly, we were looking at histology, the type of kidney cancer. We were looking at the immune system. And we were looking at markers, that B7H1, which is a marker of aggressiveness. But in fact, it's also a target now that any PD1 antibodies are using. And we, again, by this clinical selection, we got a response rate of 30%. So we doubled what was in the package insert, because that data included people like Paula with the papillary and some of the other subtypes. So the summary of IL-2 status is it's the only treatment which produces long-term multiple complete remissions. Another group of prolonged stable disease patients exist at the time these studies were done, stable disease wasn't really considered an endpoint. We now know in treating kidney cancer by studies done with the targeted therapies that stable disease is in fact a therapeutic benefit. And we can stabilize people, again, for months to years, by giving immunotherapy as well as the targeted therapies. It's a small number, it's highly selective, and it's complex. And so for me, it's what we had for 20 years, we're still going to use it, we're going to explore new ways of using it. But it tells us that immune therapy really is something we should capitalize on in taking care of patients with kidney cancer. Now, Dr. Wong mentioned this briefly, but there are some new vaccine strategies. Vaccines for cancer in general have had a lot of bumps along the road, and we've been doing it for more than 20 years. But the key is what is the antigen that the immune system will recognize? Like when we get a vaccination for measles or mumps, we know the virus, so we can target those proteins. Here it's harder to know. And so one of the thoughts and one of the ideas is this Argos trial that Dr. Wong mentioned, which is personalized immunotherapy. And it's kind of a neat idea. Basically what dendritic cells are, these are part of the immune system. They're called antigen recognition cells. They take the tumor cell and they chew it up and they spit out proteins that are characteristic of the tumor for your T cells to recognize. So it's a cell-cell interaction. But by using part of the tumor, I can't even say it, electroporated, patient-amplified tumor RNA, what you do is you take a piece of the tumor and you mix it up with the dendritic cells and then the dendritic cells say this is the tumor antigen you go after and the T cells are going to go after it. And so that's a concept of where your tumor can be the protein that your immune system will chase. So it's a clinical trial. We don't know yet whether this is the answer, but clinical trials are how we've made progress. So that's why with the Kidney Cancer Association, we're always talking about clinical trials. It's an expansion of the T cells, your own T cells and these RNA-loaded dendritic cells. It is designed to induce an immune response. It's an international study and it's basically after the kidney is removed then this vaccine is produced. So it's, again, as he mentioned, it's pseudonitinib alone versus pseudonitinib plus the vaccine. So we shall see, okay, but it's, so stay tuned. Preliminary data showed that there were durable immune responses achieved with significant increases in these T cells. Now whether that's going to lead to antitumor effect, we're going to find out. The other thing that's important at the bottom is that you need to know about when you're talking about immunotherapy is it's a decrease in regulatory T cells and myeloid derived suppressor cells. Keep in mind that the immune system has to have checks and balances. One of the side effects of some of these immune active therapies, including some of the targeted therapies, is that we can induce autoimmunity, meaning immunity to normal tissues. And so in normal circumstances, your body's immune system will go after something that's bad, like say you got a bite or something and you get a swollen lymph node and there's an immune response. And then it calms down and it goes away. And that's because other cells are saying, okay, you've done your job, turn off. So we have a push pull in the immune system. And these regulatory cells and these MDSCs can actually turn off an immune effect. And that's one of the issues with say tumor infiltrating lymphocytes is a lot of them are regulatory and they're actually turning off the immune response. So it's important to, so that's something else that we're fiddling around with and certainly the laboratory scientists that are immunologists are trying to figure out how to enhance the killer T cells and not activate the regulatory T cells. So Dr. Alter brought up the story of the checkpoint inhibitors. Anti-CTLA4 is your voice, is one of them. And it is approved for melanoma. It again takes the break off the immune system. It's kind of a global activation. There is activity in renal cell, but there was a lot of GI toxicity during the initial studies in renal cell. So kind of people have shied away from it. Part of that was just an inexperience with this drug. You know, with every new drug we have, there's what's called a learning curve. We have to learn how to recognize the problems. And I think this may have been just, you know, one of the early kind of casualties of learning how to use your voice. On the other hand, the anti-PD1 and anti-PDL1 work at a little bit further down in the immune system, closer to the tumor. They're actually, the tumor can inactivate the T cells. And so by putting that antibody in between the T cell and the tumor, then the T cell can go after the tumor again. The tumor actually can block the cytotoxic T cells. And so the PD1 doesn't have as much of a generalized autoimmune activation as does the anti-CTLA4. So as I said in the previous slide, an older population with other medical issues, we're thinking, not proven, but we're thinking that the anti-PD1 version of checkpoint inhibitor, excuse me, may be more manageable. And certainly will be a candidate for combination studies. So as I said, they're still in clinical trials. From the phase one studies, there are responders and even long-term responders who publish, but in melanoma, we don't know yet the story in renal cell. And the toxicity is autoimmunity because we're activating the immune system. So the stuff that's been published so far, and it's still early on, these were broad phase one and twos. They took patients with a lot of different cancer types, including kidney cancer. You can see some of the eight toxicities in the second bullet. They're immune related. They're called rash, diarrhea, pneumonitis. And then colitis, hepatitis, hypophysitis means they knock out the pituitary gland, thyroiditis. So there are immune toxicities. But as you can see with renal cells, small number of patients were treated. Response rate about 27% and stable disease, greater than 24 weeks, 27%. So respectable outcome. Obviously these are being pushed right now in melanoma, they've been approved for melanoma. But they're also, I think the fact that they're looking at diseases such as non-small cell lung cancer, and seeing something that looks fairly respectable should also be kind of helpful for the non-clear cell renal cell patients because a non-small cell lung cancer is not clear cell. So it may well be that this type of a broader immune activation may have applications to other types of kidney cancer. We just don't know yet. And this is the other phase one, two study that was published and again, there were responses in almost all of the tumor types. And this is the renal cell that was a little bit less than the previous study, but again, a lot of stable disease. And what I always say in renal cell, stable is good. It means there's an activity there. So we shall see. But once a drug is out there, we learn a lot more about it than we ever learned from the clinical trials. So this is just to say that anti-PD1, antibody produces objective responses in patients. Durable responses greater than a year were observed in 20 of 31 patients with melanoma. We'll see. And David McDermott has published on the renal cell cohort, again, 34 for safety, 33 for clinical activity, and nine of 34 had a greater than or equal to a partial response, one complete response. Durable out to, sum out to more than two years. So ongoing, keep, stay tuned. I'm not gonna go with that. So what are the future directions? Well, the first question is, can we step on the gas in the break at the same time? And so there are clinical trials now in development to combine anti-PD1 with interleukin-2. And what the game plan is, is to give a standard dose of PD1 and then slowly dose escalate the IL-2. And one is being done in both renal and melanoma by the cytokine working group and the group at Rutgers is opening up a study in melanoma. And I think everybody's been waiting for these studies to start to happen. And finally, I guess because one of the drugs is now both of them now are commercially available, we can get our hands on those drugs. So this is gonna be very important. And it may be a big step forward in immune therapy, we shall see. So, and ongoing investigations, I just wanna mention something that I'm working on which is the association of renal cell cancer and hematologic malignancy in the same patient or in families. We don't know why, but it's more than would be expected from the CR database. So it could be immunologic, it could be genetic, or it could be environmental. And we are collaborating with some molecular biology laboratories to at least look at the genetic component and then we'll see where things go. So, thank you very much for your attention and the opportunity to speak.