 Good morning Thank you very much for being here today and the support our Clinical research, so I'm going to give you a brief summary of immunotherapy In the current standards and in the future standards for metastatic renal cell cosinoma So as Dr. Tuneer and the Dr. Yonash already did very did very Several review of the target therapy and part of the immunotherapy, so I'm going to be able to skip some of the slides So here is the outline of my talk first I will Touch base on traditional immunotherapy Followed by clinical application of immune checkpoint therapy including anti-CDOF4 anti PD1 and anti-PDL one I will also talk about why some of the tumors actually didn't have a response to immune checkpoint therapy and What's the future like for immune checkpoint therapy? And I will also spend some time on management of immune immunotherapy related toxicity as this immunotherapies are actually Not totally benign therapies So why are we interested in immunotherapy? The short answer is immune system actually can kill tumor cells However, immunotherapy kill tumor cells in a very different way comparing to the traditional Chemotherapy under the new target therapy first it's adaptable So when tumor cells change the immune system can also change accordingly Second it's specific. It's supposed to kill only the tumor cells and as spare the the normal host cells However, as we know in this world nothing is 100% specific. So in rare situations, we actually Can hit the normal cells as well and therefore We have to deal with immune immunotherapy related Toxicity is third immunotherapy actually has memory as opposed to the target therapy and the chemotherapy So once the immune system recognize the tumor cells even after the tumor cells Wake up in Three to five years. So the immune system can still recognize these tumor cells and kill them So for example, one of the patients who were treated with a plume man has not only survived 11 years now she also had two babies, so Immunotherapy there are different strategies for immunotherapy the comments the earliest strategy was cytokine therapy as Revealed by both doctor to near and a doctor Yonash the second one is called vaccine the third one is called adopted t-cell transfer Under the newest one is called immune checkpoint therapy So far only cytokine therapy and the immune checkpoint therapy have been used in the clinic Therefore that will be the focus of my talk today So as dr. Yonash and dr. Tuneer both Revealed on the cytokine therapy include high-dose IO2 therapy and in the firm alpha or in the firm beta therapy So both high-dose IO2 and in the firm can stimulate the immune system to kill tumor cells So high dose IO2 therapy was developed over 30 years ago at that time This was the best thing in the world for renal cell Casinoma, and here is the data on high-dose IO2 therapy in patients In over 250 patients treated so among this 255 patients only 17 patients actually had Complete response, but this patients actually most of these patients can actually Survive almost over up to 10 years. So basically these patients are cured So for those patients who only had partial response their overall survival average survival is about two years and Here are the pros and cons of high-dose IO2 therapy first it can induce long-term survival However, the response rate was very low the complete response rate was lower than Seven percent the partial response rate was about eight percent. So overall Over 85 percent of patients actually didn't benefit from this therapy It can also be very toxic on average some patients can Basically gain Pound 50 to 50 pounds over a week of Of time and the many of these patients can develop heart failure Can develop septic shock and the many of them require ICU care So therefore this therapy is often limited to healthier patient and the younger patients so Interferon alpha has also been tested as a single therapy or in combination with bevacizum M So the overall response rate for interferon alpha is only about 13 percent When combined with bevacizum bevacizum M the response rate is about 25 percent and the median Overall survival can be almost doubled by the combination of interferon alpha and Bevacizum M. However, the overall survival did not increase in the combination arm So the most exciting Development as mentioned by dr. Tania and dr. Yonash is probably a mean checkpoint therapy for renal cell Casinoma and also for many other types of Malignancies, so here is how Immunotherapy immune checkpoint therapy work in order for T cells to be activated for tumor cell killing We have to have two sets of signals between the antigen presenting cells under the T cells for To be active at the same time However, the T cell also has a breaking system It known as CTOA for PD1 or PDL1 and then many others what dr. James Allison found over 20 years ago was if you use antibodies to Break this to take away the the breaking system You actually can allow T cells to be Persistently activated and therefore this will achieve a better tumor cell killing so immunotherapy one of these antibodies is called epilomab was first tested in metastatic melanoma patients so this patients On average can survive only about a year even though some of them are very young patients in their 20s or 30s So if you look at this data Over 20% of these patients can survive Almost up to five years. So this was very significant at that time Even though the response rate was very low. It's about 10% in this trial and this basically This drug actually basically gained FDA approval for it for the treatment of metastatic melanoma in 2011 So this is just one of those patients who had complete response So this patient has not only metastases in the lungs But also in the brain and because of this findings Immunotherapy was regarded as breakthrough of the year by the science magazine in 2013 so another antibody Immun checkpoint antibody is called nivolumam has also been tested in melanoma patients as you can tell This drug not only increase The progressions free survival but also overall survival in melanoma patients And that was approved by the FDA for melanoma treatment in December 2014 So what about I mean I mean checkpoint therapy for renal cell Casinoma? Epilomab was actually tested in a very small trial for metastatic renal cell Casinoma. This was reported in 2007 so this in this trial patients were divided into two groups in the first group this patients actually received Relatively low dose of epilomab the second group in the second group patients received higher those of epilomab it's three milligram per kg and So in this group fall out of Five out of 40 patients, which is about 12.5 percent of patients actually had a response So as Dr. Taneer summarized very in very detail nivolumab has been tested versus Everlimas in advanced renal cell Casinoma And I don't have to tell you very much about this because he his slides are actually more detailed in my comparing to mine so And but I just want to tell you one of this one of my patients who were treated on this trial so this was 73 year old lady who has metastatic renal cell Casinoma initially diagnosed in October 2013 and she Got treatment with Votrin, Exitinib and Everlimas for about two years, but eventually Hand disease progression at that time she had constant cough Because of the tumors in the lungs she couldn't eat or drink She couldn't even talk very much at that time. She was oxygen-dependent and a wheelchair bomb So basically at that time we arranged for home hospice for her fortunately Nivolumab was actually approved by the FDA at that time and She was actually able to be treated with nivolumab About a week before the FDA approval of the drug So just after about three months of therapy and her tumors almost Almost completely gone and then I just saw her last week. She now she can basically You know do laundry shopping by herself. So really this drug can make a huge difference in patients life so however, if you look at immune checkpoint therapy for any type of cancer for melanoma for lung cancer for Renal cell cosonoma for bladder cancer the overall response rate is about 25% so the question is why the other what about the other 75% of patients so people have been looking for predictive markers to you know to predict clinical response to this immune checkpoint therapy as Dr. Tuneer and Just mentioned but so far Nothing has been very successful So we actually took a different approach instead of looking at those 75 percent those 25 percent of patients who responded to therapy So we actually did some research to look at the 75 percent of patients who did not respond To immune checkpoint therapy. We feel that if we can figure that out We have a good chance to not only help the 25 percent of patients who responded to immune checkpoint therapy But also help the other 75 percent of patients. So For that purpose we actually studied patients with melanoma who Received epilomom therapy. So we studied a total of 16 patients among the four patients who responded to Epilim to epilomomam So we didn't find So we found that their tumors had no what's called Genomic defect in the interferon gamma pathway genes, which is a key Gene that mediate immune checkpoint therapy However, in the 12 patients who did not respond to epilimam seven nine of these patients actually had Defect in the interferon gamma pathway genes. So when we expanded this information to the what's called the TCGA database we We found a total of 267 367 patients With melanoma. So among them 134 patients actually had What's called copy number alteration a certain Genomic defects of the interferon gamma pathway genes So we found this patient those patients who Had tumor with this gene defects actually survived much shorter comparing to patients who did not have this interferon gamma Signaling pathway defect. So it looks like the tumor interferon gamma pathway gene defect is not only Not only predict Response to immune checkpoint therapy, but also Is a prurer indicator a prognostic factor for for overall survival I'm going to pass through this slide. So in the meantime another group Tony Rivers group actually found in patients who did not respond to anti PD1 or Pembrolizumam They actually developed Mutations in key interferon gamma pathway genes Net named Jack one and a Jack two. So together it looks like tumor interferon gamma pathway gene defect Is actually a common resistance mechanism for patients who do not respond to immune checkpoint therapy Including anti PD1 and anti CDOF4. We also found in prostate tumors That that's no one to not respond to immune checkpoint therapy very well. So they actually When you treat these patients with in epilomab you actually can induce lots of immune cells to get into the tumor cells However, they actually express very high level of immune checkpoints such as Vista or PDL one so as a result this patients actually do not respond to immune checkpoint therapy so with this information What so we we feel that if we can do combination therapy We have maybe have a better chance to not only increase the response rate, but also This overall survival of patients. So this graph basically Illustrate that concept for traditional target therapy you can have higher relatively higher response rate, but The resistance can develop very fast with the immune checkpoint therapy You have a relatively low response rate But have the potential for long-term survival if we can combine these two type of therapy Maybe we can increase not only response rate, but also long-term survival for for our patients So this concept was first tested by Mike Keuron in Dr. James Anderson's lab So what he found was indeed if you combine this immune checkpoint therapy you actually can Increase the survival of mice bearing different types of tumors. So and there are multiple clinical trials ongoing the most important one is actually epilomab plus Nevalumam which is an anti PD1 plus anti CTOF4 trial This is a phase one trial as mentioned by Dr. Taneer as well So when you combine nevalumam and epilomam at different doses the response rate was about 40 percent And also over about 40 percent of patients actually have stable disease So overall you can have about 80 percent of chance to control these tumors. So a phase three trial Currently here is leading by Dr. Taneer with Nevalumam versus epilomam versus Sutin is also ongoing and then hopefully we can see the the data Within the next several months and hopefully this drug combination can be approved by the FDA for renal cell Casinoma patients in the future and Another combination is with Acetanib with Pembrolizumab, which is another anti PD1 antibody has been ongoing as well. So overall 52 patients actually have been enrolled 11 patients actually discontinued therapy because of toxicity and other factors But overall the response rate as you can tell it's 67 percent, which is very dramatic However, the toxicity rate is also quite high Another combination with evalumam plus Acetanib is also ongoing So at this time of the report There were only six patients treated, but five patients actually had response at that time One patient actually had stable disease at four months. So a phase three trial Is also ongoing for this for this combination study Another combination with a tesolusumam with or without Bevacizumab versus Sutin is also ongoing at this time And it looks like the combination of a tesolusumam plus Bevacizumab actually can increase the overall progression free survival although the statistically this is not very significant and it looks like this combination can increase The response rate as well as compared as compared to Sutin versus A tesolusumam as monotherapy or single therapy So there is a another phase one study with Pemberolusumab, which is another anti PD1 antibody in combination with Bevacizumab Is also ongoing, but currently we don't have any data At MD Anderson, we have what's called a pre surgical trial By to evaluate either Nivellumab versus Nivellumab plus Bevacizumab or Nivellumab plus Ethelumab This trial is ongoing, but we recently Enrolled a total of 60 patients. We already reported part of the results at the AACR meeting So as you can tell Nivellumab along as monotherapy can have a response rate of 42 percent But this is based upon a very small number of patients when Nivellumab is combined with Bevacizumab The response rate is actually 52 to 53 percent When Nivellumab plus Ethelumab when Nivellumab is combined with Ethelumab So the overall response rate is 38 percent So as far as toxicity when we look at the grade three or higher toxicity in the Nivellumab along It's about 19 percent in the Nivellumab plus Ethelumab group the response and the toxicity rate Is 27 percent, but in the Bevacizumab plus Nivellumab arm the toxicity rate is 41 percent Which appears to be higher than the other two group. However 17 percent of this toxicity was due to known Bevacizumab induced hypertension, which is very easy to be which is very easily managed by Blood pressure medications. Therefore if you take away This 70 17 percent of toxicity here you have only 24 percent of grade three or higher toxicity, which is very comparable to the other two groups So Currently there are many clinical trials ongoing for immune checkpoint therapy For renal cell Casinoma. So there is It's almost impossible for me to list all those trials Therefore, I only want to point out a few trials that's ongoing in at MD Anderson in our department So a few of them have already been mentioned by Dr. Taneer And also this pre-search called trial There is another trial is called a tremolumab, which is anti PD L1 antibody plus cryoablation that's led by Dr. Shama and Dr. Matin and a Dr. Kendall So there is a phase three trial with a Evolumab plus excitonin versus Suton That's led by Dr. Campbell There is a phase one Wait one and two study with MG CD, which is a multiple Tyrosine kindness inhibitor and an evolumab This is led by Dr. Taneer as mentioned by Dr. Taneer a moment ago And plus there is an evolumab plus epilumab trial In the development for renal cell Casinoma by Dr. Taneer And the many other trials in the development at this time So in addition to this exciting development of immune checkpoint therapy I want to point out to you guys That immunotherapy is immune checkpoint therapy is not benign It can it often it can cause fatal immune related toxicities. The most deadly toxicity is called pneumonitis The second one is Pneumonitis is basically inflammation in the lungs. The second one is called colitis Which is inflammation of the colon as manifested by diarrhea and abdominal pain And also hepatitis, which is inflammation of the liver hyperphocytes, which is inflammation of the hyper pituitary gland and also Dermatitis, which is inflammation of the skins. So I just want to show you a few examples for pneumonitis So this is a patient who developed pneumonitis on immune checkpoint therapy. This is the CT scan as you can tell There is this inflammation diffuse inflammation in the lungs for patients with pneumonitis often you feel Some shortness of breath you can have cough sometimes you can cough up blood So if that happens you have to tell your physician immediately and then you have to come to the emergence room for Emerging evaluation and often you have to be hospitalized for For like further diagnosis and treatment So if this cannot if this is not handled very well a patient can Lose his or her life within two to three weeks a period of time. For colitis This is basically how the colon looks like with immune in this colitis as you can tell there is lots of ulceration in the colon and on pathologies Slides you can see lots of immune cell infiltration. So when a patient develops colitis often you can have Profuse diarrhea 10 to 20 times a day. This is often watery. Sometimes you can have blood in it as well You can have abdominal pain. You can even have fever So when if you develop colitis you have to come to the ER you have to call your You know your doctor come to the ER for emergent evaluation often you will get a CT scan to look at you know for For changes in the colon for perforation you need to get Infection workup to rule out some infectious causes such as C. diff and you will be admitted to the hospital to get not only antibiotics but possible colonoscopy and also And also Hydro-steroid if this is confirmed as colitis for people who develop hyperfacitis often they have this inflammation Of the hyperpaternity to regland on the MRI scan. So when you have Hyperfacitis basically all your hormones in your bodies can be wiped out So often you feel acute vision change headache Overall fatigue your blood pressure can drop to the 70s. So if you don't seek Treatment immediately. It's very easy for a person to pass out with such low blood pressure So when that happens you also need to come to the ER for immediate evaluation So any anyway in summary So high dose IO2 therapy can have long-term survival But with with very low response rate and a significant toxicity anti immune checkpoint therapy such as anti CTOF or anti PD1 or anti PDL 1 can have modest activities against renal cell Casinoma combination therapies including anti PDL 1 plus anti I'm sorry anti CTOF 4 plus anti PDL 1 or anti PD PD1 or target therapy may overcome tumor resistance. However, the toxicity is also Very high. It has to be managed in a timely fashion. So thank you very much for your attention