 Good morning everybody. So I'm going to talk about immunotherapy for the treatment of metastatic kidney cancer today So as many of you probably know immunotherapy was regarded once regarded as a Asian Therapy of you know almost the Jurassic period however recent progress in research has revived really revived the Dinosaur in immunotherapy for treatment of cancer So I'm going to spend some time with you today to review the history of immunotherapy and more importantly I'm going to share with you some exciting data in the field of immunotherapy, especially for the treatment of kidney cancer So why are we interested in immunotherapy? Well, we know immune system can kill cancer cells However, the immune system kill cancer cells in a different way from the traditional chemotherapy and the target agents First of all, it's adaptable So when the cancer cell changes The immune system can also change accordingly second is Specific so the immune system will target the cancer cells Directly and spare the normal healthy cells third it has memory So as you know cancer cells can hyphenate in your body for many years So even after 10 years of hyphenation when this cancer cells wake up the immune system also wake up Try to catch this cancer cells And there are quite a few reasons for us to develop immunotherapy immunotherapy as treatment for cancer patients first we know tumors with more infiltrating lymphocytes actually associated with good prognosis second we know that mutations during cancer Development and progression actually can create this new antigens and this new tumor antigens can be recognized By the t-cells and the immune system Through history many immunology many strategies have been used for immunotherapy The earliest strategy was to just use bacteria stimulants to stimulate the immune system Which I will talk about more in the moment The second one was to use cytokines to energize the immune system to kill cancer cells People also tried to use vaccines and adopt t-cell therapy So these two methods are not used for kidney cancer therefore. I'm not going to talk. I'm not going to talk about them today But I will spend the majority of time to talk about immune checkpoint blockhead therapy Which really has shown some great potential for kidney cancer So the bacteria products were first used by William Coley to kill to treat cancer Known as Coley's toxin So dr. Coley actually cured the first patient with this bacteria products over 120 years ago And the lead on it was found and it was interfering alpha actually that was stimulated by this call it's toxin To to kill cancer cells and he treated quite a variety of tumors and the first the most To the tumors he treated the most was soft tissue sacoma and as you can tell from this data He treated more than 100 patients and over 50% of these patients can actually can live more than five years For kidney cancer. He only treated six patients at that time three patients didn't have response The other three which is 50% actually lived more than five years So even by today's standard that Dr. Coley was quite successful So why Coley's toxin was not approved for for treatment of kidney cancer? That's because it's too toxic. So after patients receive this Coley's toxin. They have shaking chills They really become very talk very very sick Therefore FDA actually didn't approve Coley's toxin for treatment of kidney cancer And then almost 100 years later people found IO2 actually has activities against kidney cancer That's because IO2 can stimulate T cells and a natural killer cells to kill tumor cells Other than IO2 interfered alpha and interfered beta Were also shown to have modest activities Against kidney cancer as Dr. Tuneer just talked about a moment ago So this is the high dose IO2 data on a total of 255 patients 37 patients actually had response. So of this 37 patients 17 patients had a complete response But please note of this 17 patients 80% of them lived up to 10 years and beyond and for those patients who had only partial response and There are 20 of them in total So only 30% actually only about 25% of them lived to up to almost 10 years So really IO2 therapy offers the long-term survival potential for patients However, the response rate is pretty low. So the complete response rate is lower than 7% The partial response rate is lower than 15% and it is again a very toxic therapy So many patients who receive high-dose IO2 have to be monitored in the ICU setting Therefore IO2 therapy is really limited to the younger and healthier patients And then Dr. Tuneer already showed you this piece of data by combining interfered alpha and the babycesium man as you can tell from the table here the combination therapy actually can Improve the progression survival of patients, which means it delays the tumor recurrence or progression By about three months and because of this babycesium man plus interfered alpha along with high-dose IO2 were approved by the FDA for the treatment of Metastatic kidney cancer along with many target agents that were discussed by Dr. Tuneer just a moment ago So this is basically the timeline of the treatment options for renal cell Casinoma So in 1980s IO2 and interfered alpha were first shown to have activities against kidney cancer And then 10 years later high-dose IO2 was approved by the FDA And over the past 10 years 7 to 10 years also there is just an explosion of this target agents Which are really great options for treatment of of metastatic kidney cancer and because of these agents people's life People with metastatic disease the average survival has increased from you know about a year to more than two years And then this is the combination of babycesium man plus interfered alpha However, despite the recent success of this target agents, we all know that many of these patients Will develop resistance to the treatment just within months So after that we have to switch to another agent. So the question is do we have any Better therapy with longer with long-term survival potential And then that's when the immunotherapy immune checkpoint therapy enters the picture So what is immune checkpoint therapy? I Have to talk about Immunology just a little bit here So in order for the T cells to be activated for tumor cell killing It needs two sets of signals between the antigen presenting cells and the T cells the first set of signal is Delivered by the interaction between this T cell receptor and the tumor antigens bound to a MHC molecule the second set of signal is provided by CD 28 binding to B7 So in the way, this is like driving a car Okay, so the first set of signal is like the ignition system So you need to turn on the car and then the second set of signal is like the gas pedal After turning on the car you need the gas pedal to speed up the car so that you know, you can kill tumor cells however, we all know if We only have the ignition system under the gas pedal and then you drive our car soon or later You are going to run into problem because you are going to speed up and then you cannot slow down And then you're going to crash and burn So the immune system is actually very smart It actually has its own breaking system One of these breaks is called CTLA fall. The other one is called PD-1 They are responsible for slowing down the immune system after it's activated However, the side effect of this breaks would be decreased tumor cell killing So James Ellison who is the director of the immunotherapy platform at MD Anderson Found that if you use an antibody to block this inhibitor to block this breaks To take the breaks off this T cells You actually can allow the T cells to stay activated for augmented tumor cell killing And that's how the first drug epilumina is developed So epilumina is basically a monoclonal antibody against that molecule named CTLA fall here It was first tested in advanced melanoma patients Who on average has a survival of about a year just like metastatic kidney cancer However, as you can see from the data here after these patients receive epilumina Over 20% of them can live up to almost five years. I know that is quite significant So what if you put epilumina and the other Antibody that breaks anti-PD-1 which is named nevelumina So again, this is in melanoma patients as you can tell from the data here So on average, please remember on average these patients live for about 12 months But here at one year 82% of the patients are still alive by three years Over 70% of the patients are still alive and then that is very very dramatic and that's why immune checkpoint therapy Was offered breakthrough of the year owner by the science magazine So what about this therapies in kidney cancer? So based upon this first two trials at lower concentration Epilumina didn't have very much effect in kidney cancer However, at the normal concentration that we use for the treatment of metastatic melanoma patients five out of 40 patients actually had partial response For nevelumina the result is even better so at six months over about 20 about 24% of the patients actually showed partial response and the 24 patient 24% of patients actually showed stable disease So overall almost 50% of patients actually benefited from Nevelumina at a very low concentration of one milligram per kg per kg At a higher concentration the response rate increased to over 30% and the stable disease uh rate increased to over 30% so overall More than 60% actually patients actually benefit from nevelumina So what about putting those two drugs together? We don't have data yet recently. We just designed a clinical trial to combine uh either nevelumina with epilumina or baby season map, which is a standard treatment for uh kidney cancer as discussed by Dr. Taneer So we designed this three-arm trial That in the first arm patients will receive nevelumina in the second arm patients will receive nevelumina plus baby season map And in the third arm patients will receive the combination of nevelumina plus epilumina After three six weeks of treatment, they will have surgery to remove the kidney with disease and if they have Either stable disease or response before the surgery we they will continue on nevelumina So this trial actually has quite a few advantages First of all, all these patients will receive at least double therapy or even triple therapy So patients in arm one will get nevelumina plus surgery, which is a standard treatment for metastatic disease Um with the the intact kidney tumor So patients in arm b and arm three will receive triple therapy Second of all this design will allow us to collect blood samples Before and after each trial and also collect tumor samples before and after each each treatment This way we can study the biology of these drugs directly in human body And hopefully we can identify biomarkers to improve these therapies and also identify new targets for further therapy So with this target agents, we know we can prove prolonged survival a little bit and with immunotherapy We can see this tail end effect Which is long-term survival and by combining this immunotherapy agents with each other and also with the traditional target agents We hope we can not only prolong survival, but also increase the response rates in patients with metastatic kidney cancer With that, I would like to thank The collaborators from the immunotherapy platform from pathology Geo oncology and also urology But above all, I would like to thank our patients and their families For your support with our research and clinical trials And we hope and I hope we can continue to work together to rewrite cancer history. Thank you very much for your attention