 All right, our next speaker is JJ Gal. There's been a lot of talk today about the immune checkpoint inhibitors and their promise for the treatment of kidney cancer. So JJ is gonna give us sort of a summary of where we stand with regards to immunotherapy for metastatic kidney cancer. Thanks, Chris. Good morning, everybody. So I'm gonna give you a brief review of the history of immunotherapy. But more importantly, I would like to share with you some new data on the immune checkpoint therapy, which is pretty exciting as Dr. Tuneer just talked about. So why are we interested in immunotherapy? So the short answer is immunotherapy can kill tumor cells. However, immunotherapy kill tumor cells in a very different way, comparing to the traditional chemotherapy and then the new target agents Dr. Tuneer just talked about. First, immunotherapy is adaptable. So when it activates the immune system, if tumor cells change and the immune system can also change. Second, it's specific. So it targets specifically tumor cells and spare the healthy host cells from toxicity. Third, it has memory. It actually has great memory. So when tumor cells hibernate for like five, 10 years, after they wake up, the immune system can still recognize them and kill them. So theoretically, they can offer long-term survival. Through history, scientists and the clinicians have tried to develop different types of immunotherapies. This includes cytokine, vaccine, adopted T-cell transfer, adopted T-cell transfer and the immune checkpoint therapy. So I'm going to only focus on cytokine therapy and the immune checkpoint blockhead therapy today as the data on these two types of therapies are more mature. So as Dr. Tuneer just mentioned, the first breakthrough for the treatment of renal cell chastinoma was high dose IO2, which was developed in the 1980s. So eventually in 1982, high dose IO2 was approved by the FDA for the treatment of renal cell chastinoma. So high dose IO2 basically cure tumor cells by stimulating the CD8 T-cells, which is known as cytotoxic T lymphocytes and natural killer cells. In addition to high dose IO2, interferon alpha and interferon beta were also shown to have activities against renal cell chastinoma. So they do this by one, stimulating the immune system, two by directly inhibiting tumor cell growth. So here is the data on high dose IO2 as you can tell from this graph for those patients who have complete response, they actually can live for a long time up to 10 years or beyond. However, for those patients who only have partial response, the median overall survival is only about two years. And these are the pros and cons of high dose IO2 therapy as I mentioned a moment ago. So the long-term survival of 10 years or beyond is very appealing. However, the response rate is very low. Only less than 7% of patients will have complete response and only about 15% of patients will have partial response and then the rest of patients will not have response from high dose IO2 therapy. It is also very toxic. So patients often require ICU care due to heart failure or septic shock-like symptoms. Therefore, this type of therapy is limited only to what's called the healthier patients, which means for patients who are older who do not have great organ functions such as, with COPD, diabetes, even mild heart failure or renal failure. So these patients will not benefit from such treatment. And here's the data showing the interference with and without bevacizumab, which is a standard of care target therapy for renal cell cosenoma as Dr. Tenir just mentioned. So indifferent alone overall can cause response in about 13% of patients. And then when bevacizumab was added, so about 25% of patients will respond to such therapy. And then the median free survival for indifferent alone is about five months when bevacizumab was added, the progression free survival was increased to over eight months. However, addition of bevacizumab to interfering gamma did not cause any significant prolongation of overall survival. And so I'm gonna spend most of the time talking about immune checkpoint therapy. This is truly a very exciting development in treating not only kidney cancer, but also many other different types of malignancies. This was developed by James Anderson, who is the director of the immunotherapy platform at MD Anderson. So what is immune checkpoint blockhead therapies? I'm gonna give you a very brief introduction of the background of immunology. So this is a pretty difficult task, but if you just follow me step by step, I think you will understand this very well. So in order for the T cells to be activated to cure tumor cells, there have to be two sets of signals. We call it signal one and the signal two. So signal one is provided by a molecule. It's called T cell receptor on the T cells or TCR. And the tumor antigens presented on the antigen presenting cells. That's the first set of signal. The second set of signal is produced by, is provided by the interaction between two molecules. One is called CD28 and the other one is called B7. So with this two sets of signals, you can achieve a pretty good tumor cell killing. However, tumor cells are very smart. They actually can express some molecules to inhibit the T cells. And the T cell by itself can also inhibit, can also express some inhibitory molecules to curb the immune response. Why? Because if you keep activating your immune system without a break, so it will actually cause damage to your body. So there is some checks and balance molecules here. One of them is known as CTOA4, one of the breaks. The other break is known as PD1. The third one is known as PDL1, and the fourth one is PDL2. So once these inhibitory molecules are engaged with T cells, so the tumor cell killing is actually, is damaged. So what Dr. Anderson found was, when he used this monoclonal antibodies to take away these breaks. So he can keep these T cells consistently activated for tumor cell killing. As a result, you have more tumor cell killing. So that's the basics of immune checkpoint therapy. So the first immune checkpoint agent was called Iplumam, or anti-CTOA4, which is against this molecule here. So it was tested in metastatic melanoma. As you know, as you probably know, metastatic melanoma is probably even worse than metastatic kidney cancer. So on average, these patients can live only about 12 months. So if you look at this phase three data, the data alone appeared not to be very impressive because most of these patients actually don't benefit from such therapy. However, about 20% of patients will survive for up to almost five years. So considering most patients only live for about 12 months, this is pretty striking. And then when you add another agent, it's called Nivellumam, which is anti-PD1, sorry, which is this molecule here. So the result is even more striking. As I mentioned, these metastatic melanoma patients only live on average of 12 months. But at 12 months here, when you use the two agents, so over 80% of these patients were still alive. So even at almost three years, more than 70% of these patients were still alive. So this is a truly amazing result. And because of this, immunotherapy was regarded as breakthrough of the year in 2013 by the science magazine. So what about these checkpoint therapies on renal cell carcinoma? So this was the first, first two clinical trial of epilumamab or anti-CTOF4 for metastatic renal cell carcinoma. At lower dose, epilumamab actually didn't have very much activity for renal cell carcinoma. However, at higher dose, which is the standard dose as used for melanoma patients. So the response was quite modest. Only five of 40 patients actually had response, which is about 13%. What about nevelumamab, which is the anti-PD1? That's the second immune checkpoint blockade agent. So this was recently published in Journal of Clinical Oncology by Bob Malza. So as you, they tested nevelumamab at three different concentrations, 0.3 milligram per kg, two milligram per kg, and a 10 milligram per kg. And here is the progression-free survival, which is not very impressive. It's only 2.7, 4.0, and 4.2. The response rate is, for all three concentrations, was about 20%. However, the median overall survival is pretty significant. As you can remember, if you remember, the interferon gamma plus beversusumab, the median overall survival is about 18 months. Here, it's increased to about 25 months at higher concentration of nevelumamab. So there is a phase three trial comparing anti-PD1 or nevelumab against everlimbs. This trial has finished recruitment, and hopefully we can hear about the data later this year. And I hope this agent can be approved by the FDA for the treatment of metastatic renal cell cosinoma. So what about the combination therapy of anti-PD1 or nevelumam and epilumamab? Since they were so impressive in metastatic melanoma. So here is a phase one trial, basically testing a combination of different concentrations of different doses of nevelumam plus epilumam, either at three milligram of nevelumam plus one milligram of nevelumam, or three milligram of epilumam plus one milligram per kg of nevelumam. So here is the data. So as you can tell, for both these groups, the response rates were very impressive. For nevelumam at three milligram per kg plus epilumam at one milligram per kg, the overall response rate was 43%. And the stable disease rate is 24%. So when you reverse this concentration, the overall response rate was still 43%, but the stable disease rate was 35%. However, this arm was shown to be very toxic. So currently the standard combination regimen is actually nevelumam of three milligram per kg plus epilumam of one milligram per kg. So overall, as you can tell, about 60 to 70% of patients actually can benefit from such combination therapy. And if you remember the high dose IO2 response rate, it was about 15 to 20%. This is much more impressive. And again, this is the progression free survival, which is about six months. So currently there is a phase three randomized trial comparing this combination therapy with nevelumam plus epilumam versus sutent in patients who were previously entreated metastatic renal cell Casanoma. So this trial is currently open and led by Dr. Tuneer. So we just enrolled some patients during the past couple of weeks. So here is the study design. So basically this population of patients will be entreated they will also get tissue for biomarker staining, which is similar to what this lady just asked about. So this is how we use this biomarker to guide therapy in the future. So these patients will be randomized into two arms. In arm A, patients will be treated with nevelumam plus epilumam. In arm B, they will receive standard therapy agent, sutent, which is one of the best target agents for treating metastatic renal cell Casanoma. So that's the combination between the immune checkpoint agents. What about the combination of immune checkpoint blockhead agents plus the target agents? So there is one trial, a phase one trial to evaluate the combination of nevelumam plus either sutent or persopenate. So this trial, this is the trial design. So it's a little bit confusing here. So basically it's two arms. One arm using sutent plus different concentrations of nevelumam. The other one is persopenate plus increasing concentrations of nevelumam as well. So here is the result. As you can tell, for the patients who get sutent plus nevelumam, the overall response rate was 52%. Stable disease was 30%. So when patients get persopenate plus nevelumam, the overall response rate was 45%. And a stable disease was 35%. So in total, about 80% of patients actually benefit from such combination. So this is even more striking, more impressive comparing to the two checkpoint blockhead agents of nevelumam plus epilumam. And the progression, so free survival here is also increased when, so in the sutent plus nevelumam group, the progression free survival is about one year. And for the persopenate plus nevelumam group, the progression free survival was eight months. So as you can recall, for the previous trials, most of the progression free survival was anywhere between four to eight months. So this one actually increased to 12 months. We have another combination trials currently open at MD Anderson. So by testing combinations of nevelumam plus either epilumam or bevacizumam, which is a standard of care target agent for renal cell carcinoma. So this is a pre-surgical trial in patients who have metastatic renal cell carcinoma but eligible for cytoreductive nephrectomy, which is to take out the primary tumor as Dr. Wood talked about earlier today. So in this trial, patients will be randomized into three different arms. So in the first arm, the patients will be treated with nevelumam only every two weeks for three doses. After that, they will have surgery to take out their primary kidney cancer. So if they derive clinical benefit before surgery, which means if they have clinical response or stable disease, after surgery, they will still be given nevelumam as maintenance therapy. The second arm is, on the second arm, patients will be treated with nevelumam plus bevacizumam. And this is also every two weeks for three doses followed by surgery, followed by maintenance therapy. On the third arm, patients will be treated with nevelumam plus epilumam. But this is every three weeks because these two combinations is more toxic. So for two doses, followed by surgery plus maintenance therapy if they benefited pre-surgery call prior to surgery. So the advantage of this trial is it will allow us to collect pre- and post-treatment blood and also tumor tissues. And in this way, we can study the biology even in a very organized way to inform us what patients will benefit from this therapy, what patients will not benefit from this therapy if they don't in the future. Whether how can we basically put them on a different type of treatment. So one thing I want to bring to your attention, that's immune-related toxicity, which is also known as IRAEs, which stands for immune-related adverse events. So you will probably hear about more and more. So despite the very exciting data on immune checkpoint therapy, they are also associated with very significant toxicities. And this toxicity will require a very, very good communication, very timely communication between our patients and as a clinical team to manage these toxicities. So here I listed the five most common, but also potentially fatal, toxicities. The first one is called pneumonitis, which means inflammation of the lungs. So when patients experience shortness of breath, even very mildly, even on exertion, especially with exertion, we should know about this right away. There's just a few days of delay can cause death. So this is known nationally. The second one is diarrhea or colitis, which means inflammation of the colon. So if you have just one or two episodes of diarrhea on this type of drugs, all abdominal pain, cramping, you need to cause immediately. So if you delay for a few days, so this can be very difficult to treat and then this can also result in death. The third one is called hepatitis or inflammation to the liver. So this one is difficult to find for the patient because often you just have some vague symptoms, like fatigue, some pain in the right abdomen. So but often you don't feel very much unless you did lab tests and then reveal elevation of liver enzymes. So this one can also be fatal if it's treated too late. The fourth one was called hypophocytus, which means inflammation of the pituitary gland. This one is also very dangerous. So if you experience headache, acute vision change, fatigue, or if you measure blood pressure at home, you find your blood pressure is in the 70s or 80s. So that suggests you might have this hypophocytus. So the danger of hypophocytus, it drops your hormone, including cortisol, including the thyroid hormone. So when cortisol is dropped, so your blood sugar can drop and then your blood pressure can drop dramatically. This way you can pass out very easily. So we should know about this as soon as possible. So even a day can make a huge difference here. The fifth one is very common. Most patients actually have certain type of dermatitis or rash on your body. So if it's mild and it does not progress very much, it's actually very easy to treat. You can just put some banageal cream on it or hydrocodicone cream. However, if it gets worse to the point that you have blisters on your skin, you have to come to the hospital. You have to cause immediately, come to the ER for evaluation. So because this can progress very fast and then before long, you can have your skin slough off your body and at that time it can be fatal as well. So the key here is if you have any of the symptoms, you just tell us early. And then once we know about this, we will do a bunch of labs doing some very quick tests and then we will put it on high dose steroid. Most likely it will be fine, but if it's delayed, it's very, very dangerous. So in summary, high dose IoT therapy provides long-term survival, but with low response rate and a significant toxicity. Anti-CDOF4, anti-PD1, there is another one is called anti-PDL1 that I didn't talk, but they each have modest activity against renal cell casinoma. However, combination therapy, including anti-CDOF4 plus anti-PD1 or anti-PD1 plus the target agents provides a higher response rate with a pending survival data at this time. So immune-related toxicity have to be managed as early as possible. So I would like to thank you very much for your attention and also I would like to thank our patients for participation of this clinical trials as you can see from this history. So this is, all these amazing advances was essentially done on our patients with our patients and actually by our patients along with our research team without your support, these advances could not have been possible. So thank you very much. Any questions for JJ? Thank you.