Why does immunotherapy not work for everyone with kidney cancer?

thank you and so you know as I get started I just wanted to share a quick story with everyone that I myself am a cancer survivor I had a melanoma that was diagnosed on my face when I was a resident and my wife had just given birth to our first daughter and it was just an absolutely terrifying process I met with several different surgeons had several different consultations and while I spoke the medical language it was still all confusing and overwhelming and I really wanted to base this talk and I really created a brand new slide deck for this individual meeting with the hope of just making everything as transparent as possible try to remove as much doctor speak as I possibly could and if questions are emerging either during the talk or after I'm happy to take any questions that come out so it really is my honor to be here today this is a complex topic because I believe we really are just scratching the surface of immunotherapy and amino oncology there are a lot of agents that are coming down that are very exciting that by themselves may not have a huge role but in combinations may prove to be tremendous game changers so the title of my talk why does the immunotherapy not work for everyone what are predictors of success can patients be cured disclosures and so as we've discussed and you've heard so far prior to 2005 our surgeons played the biggest role by far in managing of this cancer and they still very much do from the medical oncologist perspective what could we add with cytokine based therapy and these are basically therapies that made people feel like they had the flu and they really were an all-or-none phenomenon they work for some about five to seven percent of patients who received high-dose interleukin 2 with metastatic disease would never relapse again and they were cured with a very intensive but short period of time however during the initial studies 1% of patients who were treated died from being treated and so when you think about 5 to 7 percent cure with 1 percent risk of death that's a very very narrow window chemotherapy have been tried and deemed a failure radiation had been tried and at the time conventional radiation had not shown any effect and this is one of the slides and I'm going to show very few of these kaplan-meier curves but basically if you look at the y-axis which is the one that goes from top to bottom a hundred percent of people are alive when you start is your percent and this is for a continuing of response so a hundred percent of patients are at the top 0 percent of patients are responding and then duration on the x-axis at the bottom is in months and what you can see here is the patients that have the complete response many of these patients are never going to have recurrence of disease up to ten years after however I caution everybody in the room including the medical oncologists in the room and the surgeons you can see that patients even in complete response there were patients that relapsed and while we are very excited about the complete response that's being seen with the combinations of immunotherapy until we have longer term follow-up we can't call all of those patients cure and that's important so clear cell renal so others have shown this but this is a me she and I when we have patients come into clinic we draw this out and I think about this in very simplistic terms so if you look at a clear cell cancer cell VHL and so VHL basically is a gene and this gene was discovered in the 1980s and was named after two famous scientists that were working on kidney cancer this gene produces a protein also called VHL and this controls and regulates hip hip is your oxygen sensor in cells so in ninety percent of clear cell renal cell carcinoma VHL is lost these are both the film the familial type which is the VHL syndrome and then in also sporadic cases and it can be lost in a variety of ways it can be silenced the the protein itself can be malformed there's a lot of different ways that this can be impacted but when it's lost what happens if starts building up and so your basically your cell is signaling I don't have enough oxygen so it goes into the nucleus and it spits out growth factors and so I think about these like fertilizer for where the tumor lives and so one of the most famous is veg F and veg F seems for vascular which are blood vessels endothelial which are blood vessel lining cells and growth factor again is fertilizer on all these blood vessel cells they have receptors that are looking for this signal and this causes these blood vessels to continually sprout and form new blood vessels which is why clear cell kidney cancer is an extremely vascular tumor we can block veg F with Bevis is a map we can block these with a variety of different DK eyes and so in the era of 2005 to 2015 this was where the real progress was made so the immune system is incredibly complex but trying to break this down into more simplistic terms we have an innate immune system and so if you go all the way back to flies & insects and then earlier lizards you're gonna see an eight immune system and then in more advanced species including humans you begin having the adaptive immune system so the innate immune system neutrophils these are your first responders anytime there's some a bad looking you cell the neutrophils rush in they release a lot of chemicals and this is why when you get a cold your initial days are pretty miserable as they're secreting everything trying to control it macrophages these are the eaters of damaged cells eosinophils they help you target parasites and allergies the reason why I think we have so many allergies these days is we live in a world where we disinfect everything we no longer have parasites so aureus nfl's don't know what to do with themselves dendritic cells these are cool cells these basically help pick up dying cells and debris and their goal is to show off to t-cells what they found in between we have these natural killer cells and there's a lot of really exciting research looking at these their goal is to recognize self versus alien and so if you're a cell that's not supposed to be there their goal is to take care of it the adaptive immune system these are B cells and the B cells when they're triggered produce plasma cells which are antibody factories and then we have T cells and these are the smart killers there's a very delicate balance because you can have malfunction on both sides over activation and so I think about tuberculosis tuberculosis kills people because you have an infection that the body is trying to control and contain and just cannot but the reason why it was called consumption for many years was because you would consume everything in your body all of your energy stores trying to get rid of it overactive can also be due to inflammatory conditions like autoimmune diseases such as rheumatoid arthritis and lupus we also see inflammatory conditions lead the cancer so Austria of colitis has a very high write rate of colorectal cancer under active death due to infections inability to heal wounds and also potential development of cancer so there is this how do we achieve this balance there is an incredibly complex communication that occurs between cells tissues organs chemical signals are constantly being sent out trying to make sure that everything is is in status quo some of these signals stimulate the immune systems while others will knock it down some of the immune cells are active in targeting cells and others actually suppress cells the amazing thing is everything is plastic and so cells can change from one to another depending on their environment and so part of our issue with all of this is when we get a sample even if it's a tissue biopsy we're seeing a window of time we're not seeing the evolution when I'm showing at the bottom where it's just M that's again the macrophage and this is way over simplified because as we continue to explore we continue to find more and more subtypes or macrophages but in simple terms m1 tend to be good macrophages that you want to have around m2 our negative regulators of the immune system t-cells there's a variety of T cells T cells became very imprinted in everyone's mind during the age during the HIV epidemic and we think about t1 these are cd8 T cells and t2 these are cd4 T cells cd4 are the ones that are targeted by HIV we also think about these t1 cells as being our T effector cells and then we can have T regulatory cells again these are ones trying to help suppress the immune response which is good because you don't want to have immune system that's again always turned on the cancer finds a way to cause these regulatory cells yet help keep away the good immune cells from targeting the cancer cells all right so let's briefly talk about t-cells and so when we're all growing up in our very early stages after we're born we're born with a thymus and most of us have had our thymus disappear by adulthood but during the time in the thymus these baby t-cells and I made them a little tea are constantly being exposed to self antigens and if they react to self antigens they're removed because you do not want to attack yourself you want to attack things that are foreign and we literally have millions of t-cells that then eventually are able to make their way doubt most of these t-cells are either at times in circulation we have t-cells that end up in the gut those are a little different than the standard t-cells we also have T cells that make it into lymph nodes so let's think about the common cold so the common cold we have infected cells that are virally infected and these cells are trying to figure out ways to get a flag up that says help me and so what happens you get this Russian of the innate immune system shown here in purple and yellow these are some of the antigens that are inside these virally infected cells and what this flag at the top is is one of these antigens that's being brought up to the surface so you get this Russian of these killers or these neutrophils and these cells can die in a variety of ways these cells can die by something that's called apoptosis which is a shrinking of these cells which then can be munched up by the macrophages you can also die from necrosis and necrosis is the split opening of these cells which is much more immune stimulating dendritic cells can pick up debris there's a release of cytokines and chemokines these are chemicals that help sound the alarm we have learned over time and Jim Allison did a lot of this work at during his time at a variety of places he's now the chair of our immunology department at MD Anderson but these signals are the dendritic cell has to present its antigen to the t-cell there also has to be a second signal that allows these T cells to activate and this signal is between cd28 on T cells and cd8 T on these dendritic cells or what's known as professional antigen presenting cells if the signal occurs this rusting T cell can turn into a effector T cell and have some of these then go kill the virus and then there's a potential to generate memory and if you generate memory this is why if you're exposed to the same infection again you're unlikely to get it and that's why vaccines in general have been the greatest thing that has ever come out to help protect the population as a whole against things like polio and measles and other infections that killed many many patients and children however when cd28 comes up ctla-4 comes up soon after and it blunts that immune response because again you want to be sure that this is worth going after we can block ctla4 and this is your paluma map which has been discussed earlier and other agents that have been in testing as well and when this is blocked again you have the better chance to then generate these T effector cells and potentially that immune response as well the pd-1 PDL one which has been talked about pd-1 is programmed death like our program death receptor 1 and program death ligand 1 and so these are mostly in the tumor micro-environment the ctla4 is more on lymph nodes and so it's considered an earlier earlier event and so I really liked Mike slide earlier today with the police officer because I think that's really true you really help get more of those police officers in with ctla4 but the police officers that are there are helped by this PD one PDL one interaction so I think about the PDL one as a camouflage for the tumour the other thing and I'll show this a little bit later is PDL one can also be on effector T cells or also on other immune cells in its environment and those are basically a sleepy exhausted signal so kidney cancer still is a little bit simpler because we have Nivola map here but I also treat patients with bladder cancer and in bladder cancer we have five agents that all are attacking the same pathway so we have PD one and then we have PDL one antibodies all of these there's a variety of these that are also currently in testing in renal cell and there's a good chance that some of these drugs may come online in the not-too-distant future so where do we stand with Amino therapy in 2018 for kidney cancer so opdivo or Nivola map approved in 2016 it improves survival as compared to patients who are treated with everolimus which is an mTOR inhibitor in patients with metastatic clear cell kidney cancer 22% of patients had response I don't think that's the whole story because I really believe that more patients and 22% have benefit the issue with response is when we think about response on cancer trials that means that patients have to have a 30% reduction in their cancer burden measurements when we take measurements this was developed in the era of chemotherapy and it doesn't apply as well to immunotherapy the side effect profile of nivolumab was very reasonable 8% of patients had to stop therapy due to major side effects and when they looked at tolerance has compared to everolimus who was much better tolerated so nivolumab plus apple of a map was approved earlier this year and I was actually a typo it's 2018 not 2017 and it's based on the checkmate - one for study and so patients on this study were given either Nivola mAb a nipple in the map or given sunitinib 42% of patients had response however when you compare the rate of patients that had major events 22% of patients had to stop therapy due to the serious immune related toxicities we are very excited about a lot of the combinations that are quickly coming down the pike that are combining the veg F tki therapies with immunotherapy their response rates that we have seen in phase one and two studies have been very high and multiple phase three studies are soon to be reporting and there are going to be some that will be reported at a conference in October which is the Europe the asthma or European European Society of medical oncology so can we predict response the answer really is no we're still having a major problem here it seemed really simple this study led by dr. T'Pol Ian it seemed that if you had PDL positivity in cancer cells your chance of responding was was real and we saw this across a variety of cancer types this included melanoma kidney cancer and lung cancer if you are negative on this initial study no response we have learned over time though that that's just not the case we're struggling in some ways because every company has a different companion biomarker everyone has a different antibody everyone is testing different things some companies are only testing tumor cells other companies are only testing the infiltrate for PBL positivity and others are testing both even when the same company is testing and different or doing trials and different tumors they're using different cut points and even sometimes in the same type of cancer they use different cut points and when I say cut point what does that mean that means that a patient is considered positive if they have a 1% staining and what I can tell you is if you sneeze on a slide it can look at it's 1 percent positive some companies are using 5 percent some are using 10 percent some are using 25 percent so it's all very confusing so the PDL status in kidney cancer so this had been shown for a while that patients that have PDL positive tumors and this is really in the era of the TK i's prior to the introduction of the mean checkpoints bill is felt to be a negative prognostic marker so what does that mean patients that were positive here were less likely to do well with treatment or were it meant that they basically had a worse overall outcome if they had this as part of their initial diagnosis on staining when the checkmate su-25 was tested which was again to volum a versus everolimus patients in both groups did worse if they were PDL positive it did not impact their likelihood to respond and Nivola map still did a little better than ever limas on that side of things so it was not decided that we should need to check patients for PDL positivity checkmate 2 & 4 looked encouraging because patients who had PDL positivity did better with immunotherapy as compared to submit nib and patients appeared to have a higher rate of complete response if they were positive as compared to those who are negative so perhaps we're overcoming the negative prognostic marker of the yell positivity this is so confusing to me because in melanoma it's the exact opposite conclusion if PDL positivity was simple all positive positive patients would respond and all negatives would not but it's not so and part of the reason why and this is a very nice illustration by Pam Sharma and Jim Allison from MD Anderson his PDL positivity is dynamic and what does that mean it means based on what a patient is receiving at that given time or based on what's going on in their body at that time PDL can be positive or negative so a patient can flip their status as being positive or negative it is not static the other thing that is so interesting is even if you sample multiple areas in the same patient at the same time you may get a different result what they're showing on the figure to the right is a tumor that is invaded by multiple different immune cells these are called the hot tumors and then at the top these are considered cold tumors and again the cold tumors are felt to be less likely suitable for just targeting pd-1 or PDL one I also treat patients with testicular cancer and they're a huge number of patients will be PDL positive but we're not seeing any responses using pd-1 or PDL one agents in us because they have no immune cells they're always like this slide so this is an example in melanoma melanoma and kidney cancer have been cousins for a long time due to the use of high-tech high-dose interleukin 2 so I always like to keep track of what's going on in melanoma so in melanoma about 50% of patients who have cutaneous melanoma will have a beer a few tation and the first breakthrough drug that came out for metastatic melanoma was targeting b-raf and what you can see here is in the top two slides you see cd8 positive and cd4 positive and the pink are the immune cells that have infiltrated into this tumor six weeks into treatment with this drug which is a b-raf inhibitor you see this massive influx of immune cells and then when you see when the patient's cancer grows because patients will eventually lose the response with these drugs all those immune cells are gone and that tells you that you have a window to see what actually is going on with within these tumors and if a biopsy is done that progression you may not learn why the patient is progressing so I mentioned earlier that PDL can cause exhaustion and T cells and so if we are able to target this again we're able we're able to potentially restore their functionality but interestingly what a tumor is secreting into its environment also is influencing PDL status and we've there's been some very nice modeling that's come out this showing the high levels of bad Jeff can cause effector T cells to produce PDL so why do patients maybe not respond well we've seen that effector T cells can malfunction we need these t cells to be able to secrete they're killing basically their kill function and one of their main kill functions is producing something that's called interferon gamma and there's been some very nice work that has shown that these T cells can have a malfunction in that pathway so that they can't do their job mi a means that they're missing in action they're just not present we've also found that there's many many more checkpoints than just ctla4 and pd1 and PDL one from a tumor standpoint what are we seeing tumors can evolve they can figure out ways to get around and to bring up other immune checkpoints Houdini they can hide it can do a better job of not showing off antigens that they may have and they can continually work on camouflaging with other immune checkpoints they can build up a fortress they can bring in a lot of negative immune cells to help keep good and mean cells out and there's a potential that some organs in their environment may be worse and we think this may be the case with potentially liver and bone and potentially brain so what else is going on so we're exploring if we can kill cells through various mechanisms freezing and cooking high-dose radiation to help cause some of this necrotic cell death to be more immune stimulating or exploring additional pathways that may be important to kidney cancer and we're trying to work on blood based assays to hopefully try and limit biopsies as we move forward so do we cure patients with modern immunotherapy I'm gonna give a couple of cases where I think the answer to this question is yes so this is one of my patients 66 year old male who came in with fatigue weight loss not feeling well very rapidly growing breast mass I don't know if my right here this is a tumor they actually at the outside Hospital a diagnosed him with triple negative breast cancer so male breast cancer is something that we see quite commonly at MD Anderson 90 Oh somewhere around 95 to 99 percent is hormonal E+ so you're taking a rare cancer and even making it more rare so who's referred to our breast group they did additional work of yet bone metastases large kidney mass he had tumor within the liver so when I saw him you was not feeling well he had lost nearly 20 pounds poor appetite coughing pain having worsening anemia he had elevated neutrophil count he clearly had pooris disease we did a kidney biopsy extensive necrosis with clear cell features and that looked the same as the breast biopsy so we actually put them on one of the clinical trials and so this is a patient's breast mass you can see it here and then see it melting away you can see his baseline scan and what I want you to look at here is see how in this tumor there's this white area and then this very dark area this area right here to keep an eye on because that's what these tumors often look like centrally necrotic but when you look at it over time that now just looks all the same it looks very cystic in nature he underwent surgery and sure enough that entire large tumor there was no viable tumor remaining after just six weeks of treatment so that patient remained on therapy for a while we eventually took him off because he had elevated pancreas enzymes and was developing some symptoms he's been off of all therapy now for over 18 months and is doing remarkably well back to work full-time this is a second patient patient presented with hoarseness not feeling well very very big burden of pulmonary metastasis large kidney primary in place yet anemia his calcium was quite high not feeling well at all he's also put on trial he gets two doses of Nivola mab and that paluma mab his lung metastases mouth his kidney again becomes more cystic in nature my new focus of residual cancer with therapy effect at the time of surgery resumes Nivola map we can virtually see no sign of his cancer he's feeling great so are these patients cured we're very hopeful long-term data is lacking and so we really want to be convinced as a community that these systems these patients will continue these responses for a long time and I think many questions remain how long did treat the great responders are complete responders the same as the deep par 4 responders and how do we select the best treatment for each patient so the evolution of treatment since 2005 has been clearly astounding and how do we learn and continue to improve we have to trust each other we have to partner together we have to advocate we have to fight every patient is an individual you are not a stat and we have to fight as a community and what's the community its patients it's their caregivers its physicians its nurses its pharmacists it's everybody in the team it's also our government it's industry everybody plays an important role and we make progress with government funding industry and philanthropy all agents that have been approved to date only made it by participation in clinical trials and there remain substantial work to be done but I feel that the future is truly bright and the fight against this cancer and with that I'll thank you and I'm happy to take any questions [Applause]