 So we are running a little late, but I think maybe we'll have our meeting we'll have lunch We'll shorten our lunch hour and maybe eat in this room so that you can stay on time So it's my pleasure to introduce our next speaker Alice van Alice is a colleague in medical oncology She's an assistant professor of medical oncology in addition to seeing patients with kidney cancer Alice's Alice focuses her time on really Trying to figure out how treatments work how effective are they she spends her time looking at blood and trying to find better ways to Monitor our response to treatment. She's engaged in many clinical trials here at Stanford And it's really a pleasure to have Alice talk to us today on her work on kidney cancer Thank you Alice again for being here And thank you for your attention. I think I'll be done in 15 minutes, so we'll make up some time before lunch It's really a pleasure to be here today and to answer a question that's on all of our minds You've had great talks today about the state-of-the-art treatments and where we're going But once we've gotten we've made a decision and chosen a treatment for you. How do we know it's working? And how can we do that to do better so we need better answers for every step and you've heard great talks about how to get Better diagnoses with and how to get better treatments and outcomes with nephrectomies how to choose your first treatment I'm gonna focus on this. We've chosen a treatment whether it's first line second line or third line for advanced disease and All the talks have been showing you CT scans. That is our gold standard That's what we do is we treat you for two to three months And then we see literally with the ruler if things have gotten smaller on a scan so We use these scans for standard evaluation to determine your stage when we're first diagnosed CTs are our mainstay, but also MRIs and bone scans. We choose your systemic therapy and Systemic therapies as you've also heard are these number of different things immunotherapies tumor cell growth and survival inhibitors the everolimus Intense or alimus as well as these inhibitors of blood vessel formation So when we have all these therapies to choose between We want to know if they're working once we've started them now. How is it that we do that? And how do we know that it's working in your tumor? What we want to do is measure the tumor response when we give you a drug that's stimulating your immune system We would expect that there's an infiltration of cells into the tumor and that those start helping to gobble up the tumor cells Or for giving you a drug that's supposed to decrease the blood vessels that feed the tumor Then we should expect that there's decreases in blood vessels and vascularity in the tumor But right now our measures with the CT scan can't tell us that detail of information It's literally a ruler measurement about the diameter of the lesions And that's what we're measuring we're measuring size on our standard reevaluation scans And the reason it takes two to three months for these repeat scans is because it takes that long for something to shrink Just for one millimeter of tumor That's already billions of cells, but the love that's the limit of our resolution for CT scans and what we really rely on It gets even murkier when we're talking about our specific kidney cancer treatments because a lot of our treatments don't necessarily even shrink tumors We've said to you many times, you know, what if it doesn't shrink? That's a win We just want to prevent it from growing so looking for shrinkage might not be the right thing Like we said it takes eight to twelve weeks to actually heart halt the tumor growth and see it start shrinking And as we just heard with nevolumab a small percent of tumors actually look bigger the pseudo progression phenomenon Before they stabilize or shrink and if we're doing, you know a scan at eight weeks And it looks a little bigger and then we want to treat for another eight weeks or even up to six months What if it really was progression this whole time? We'd hate to lose all that time, but right now that's the best we have So you've really key questions are how do we distinguish the difference between these changes and tumor size? And what are some of the things we can do? Well, as I just hinted, it would be great if we could couple. It's kind of very echoes Okay, all right A new more direct approach would be if we could add to the CT scan tumor diameter measurements if we can add measures of activity of the cancer pathways whether it's activity of the immune system kind of getting at the question you just asked or Activity of the cancer pathways that are fueling the cancer. So that's the focus of what I'm going to talk about today And which cancer pathways should we be looking at? Well, you heard that seven out of our 10 targeted agents approved for kidney cancer Suppressed the growth of blood vessels that feed the kidney tumors. That's this angiogenesis. And this is the list of those drugs Well, how can we quantify angiogenesis the blood vessels? We have a study at Stanford that uses something called a 4d CT scan So it's called a dynamic perfusion CT And it's a special CT that measures tumor blood flow So not just the diameter of the tumor that added its measurements of the flow and the blood volume by measuring how things change over time In terms of the perfusion of lesions and how leaky the vessels are This is actually an approved thing But it requires special scanners and software and it hasn't been proven to be better than our diameter measurements yet especially for kidney cancer So our clinical trials open to offer this kind of scan to our patients here at Stanford that are taking any of the anti angiogenesis drugs And we do a scan before we start the standard treatment Another one one week after treatment because we're really going after the one week time point We know that your blood vessels start changing within days of starting these pills While it takes eight to 12 weeks for them to shrink on a ruler measurement We expect that after one week of treatment we can start seeing changes in the vessels So wouldn't that be great if we could get a hint earlier on? And then we repeat a third scan at the standard time between eight to 12 weeks of treatment Which is when we usually do a CT scan and the goal of this study is to determine if blood vessel measurements change at one week And if this can predict the 12-week response by standard CT So last year I told you about this study and this year I can show you some of our first results From me and Ia Kamaya my radiologist and our study coordinator Tommy is I'm sitting in the back and you're going to hear more from him about the things that he does So this is an example of our perfusion CT results This is our standard CT scan the black and white scans that you've been seeing And dr. Kamaya circled for me the adrenal Metastasis that we are watching and treating in this patient When we add the perfusion measurements you can see you can see That it adds areas of high perfusion in the spleen which is here in that adrenal met which is circled As well as you can see here's the blood vessels in the liver And you can see the areas that are well perfused in the liver and areas that it takes a little longer to Perfuse as the blood filters through the liver And so what we can see is that in our first patients now This is only nine patients five of them had stable disease and this is zero so when we did the one week scan The vessels decreased on average for the five for the four that progressed And again, we couldn't see any changes in size yet at one week But those that progressed that were found to progress at three months on the standard scan At the one week we saw that they stayed at zero They didn't really have much of a change now There's big error bars and even though we got a p value of 0.04 This is not yet clinically significant So we're continuing this study to see if we can get early hints And if this might be one approach out of many that we can try to add to a standard CT scan to get more information About what's happening in you early when we've started a treatment What's another way well even more directly like we just like dr. Shaw just said We can analyze the cells what better way than to look directly in the tumor cells if possible And what do we want to analyze in those cells? There's been a lot of excitement in the news and in science about analyzing DNA the code That codes for all of our processes in our bodies There's also a lot of excitement about studying RNA DNA remember is made into RNA and then RNA is made into proteins But it turns out that all these small molecule inhibitors or antibodies that are treatments all of them are actually targeting proteins So while looking at DNA and RNA is very important and can start giving us predictions of mutations that might or might not respond To see if you're actually responding if our drug has actually gotten onto that white flag and taken it down We need to look at the protein level Well, that's a really hard thing to do Serial biopsies are what would be required in order to get enough tissue to analyze proteins Right now our protein technologies require a million cells to make a measurement Or if you're trying to get a single cell measurement you have to do these Extensive processes to digest a solid tumor into one cell before you can make that analysis So we're not Ideally we don't need these large biopsies and if we can use nano technologies to get away with analyzing tiny numbers of cells That might give us a way to measure the proteins and look much more directly at how things are changing over time So i've developed the use of a new nanotechnology that can quantify panels of proteins in patient cells We use a peggy sue instrument So this is a picture of the instrument and all the measurements take place in these tiny micro fluidic capillaries And that's the secret that allows us to do a lot of profiling with just a very small amount of input We run 96 tubes of these capillary tubes at the same time and it's automated And that's really key because when you're doing things by hand there can be human error in all your measurements But when a machine does it you can build in the precision So that makes it highly reproducible and we can start getting answers in four hours So can we use this nanotechnology to measure proteins and tiny numbers of kidney cancer cells? Yes, we have shown with a huge collaboration including dr. Leppert and all of the investigators in the room today That we can determine signatures of kidney cancers using this nanotechnology And we're collecting and profiling tumor tissue from nephrectomies So maybe some of you in this room have participated in that when you got your kidney out And from radiology guided biopsies and with tomi's tremendous help He goes into the operating rooms to help us get these specimens. We've collected more than 300 specimens And what we do is we sample both the tumor itself This is a picture of a needle where we suck out tumor cells from the from the tumor As well as non-tumor cells from the normal kidney when it's come out so we can compare How your tumor signature is different from your normal signature So analysis of biologic response like I said if we could do that in this period When you start your first treatment and do it before our standard eight to 12 week tumor reassessment That could be one approach if we could get tiny numbers of cells from your tumors Before and early during treatment in real time see if we're hitting the target in your tumors And then see if that can actually predict our 12 week standard measurements That's the subject of a grant that just got submitted to the NIH Ideally, we don't even need to poke your tumor Wouldn't it be great if we could do things minimally invasive with either finding elasporates with a poke Or a blood draw that occur after administering therapy So that's a clinical study that we have ongoing is to combine these different kinds of measurements and imaging To see if we can get better predictors of if things are working So we have a lot of patients that are participating in this blood draw study too Where we get two to four sometimes extra tubes of blood at your visit And thank you, we've enrolled more than 150 patients so far that are participating in this So this is going to start really generating some exciting data Now can we do this when we're developing new drugs? Wouldn't it be great if we could find direct tumor measurements in a new drug So that we know exactly what to measure when that drug gets approved The goal would be again develop biomarkers from blood ideally that determine response earlier than eight to 12 weeks That can help accelerate the development to the new drugs because right now to evaluate a drug in a phase one Or two clinical trial. We're still using our ruler measurements And if it doesn't shrink we never know why not if we could look in the cells We can see the drug got there or not And if the drug got there, did it actually cause the tumors to stop growing? Did all the processes stop or did they still keep metabolizing and growing? And so that'll help us understand personalized therapy for advanced disease But also help understand why drugs fail and that's something we really don't know Every, you know, I've always think to myself when we see each other in clinic Why didn't that work and what could we do to make it better for the next drug that we try? And right now we don't have a way of answering that So that's why we really are trying hard to do these molecular measurements So I'll give you an example of how we're doing this for CB839 the scutaminase inhibitor that we just that Sumit already brought up It would be ideal if we could analyze changes in tumor cells by fine needle aspirate or blood draw That occurs after administering a new drug like this glutaminase inhibitor Just to remind you this drug inhibits a glutaminase enzyme Which decreases conversion of glutamine to glutamate and glutamate's an alternate energy source to glucose for your tumor cells And what we would want to do is beyond measuring the ruler measurement We'd like to see if glutamate is actually changing over time in your cells And so I collaborated with Eric Mitra in radiology to do this with the novel kind of PET scan So he has something called an f18 fspg probe and that's an imaging agent for glutamate. It's basically Um, let's see. Yeah, it's basically a PET probe where we can inject this fspg And it shows you how much glutamate is being utilized by specific tissues or tumors And this is comparing it to the glucose PET scan So we know in kidney cancer regular FDA approved glucose PET scans are not always authorized for our patients because only about half of them actually take up Regular glucose for these PET scans And this is an example of a patient on our study of the glutaminase inhibitor who got a regular glucose PET scan And this black spot is a lymph node that had tumor in it. We can measure it on the CT scan with our ruler When we look for dark spots the darker the more Glucose it took up we see it only took up about a unit of 3.7 So barely above just the normal blood vessel next to it when we tried our glutamate probe You can see that it took up 15.9 Units and it looks much darker. So for this patient actually it turned out that the glutamate probe Picked up the presence of tumor better than the regular PET scan with a glucose probe And after starting the CB839 treatment we saw that it was stable. It didn't get brighter, but it didn't get lower So in fact this patient did have stable disease and we looked across the patients the 21 patients that have been reported from this study so far 52 of them had stable disease They didn't change and one patient had tumor shrinkage and this was presented last year and this is the drug that Has really easy side effects. So we thought that would be really cool to To synergize it see if it synergizes it's going to be great in combination So one of the two studies that samit mentioned is combining the sclutaminase inhibitor with abdivo nevolumab the pd1 inhibitor And the theory is your T cells need glutamate as an energy source and they really love glutamine to make glutamate So if we decrease the glutamate Production then the glutamine which is its precursor increases and so there's more glutamine around for your T cells to use And so that's the theory behind combining cb839 with abdivo And if affinitor the everlimus is targeting one mTOR energy pathway and we combine it with Targeting the glutamate pathway could that work better and there's preliminary data for that as well So this is now going into a randomized phase two study So unfortunately, we're not going to be able to do this imaging anymore at stanford because dr Mitra my close collaborator in radiology is leaving us for oregon health sciences where he's going to be the division chief for nuclear medicine But there are other up and coming things to keep our eyes open for so We have a stanford center for nanotechnology excellence. It's been in existence now for um 12 years And i'm the leader of the clinical translation for this center So that means i work the chemists work with the chemists who are divine Who are making all these new smart nanoparticles and i help them figure out okay Well, what cancer should that be used for and how is that really going to be tested in a clinical trial? So i'm just going to share with you three things that are up and coming And then i'll end so the first project is this chemist dr Jung homerow Who is visualizing tumors with self assembling and disassembling mark nanoparticles? So you can inject one piece of a nanoparticle and it gets into the tumor cells You inject another tiny piece of a nanoparticle and it gets into the tumor cells But only in the tumor cells can these nanoparticles attach and give off a signal that we can see with a scan And then he's working on not once they get in there Let's have them disassemble so we can just excrete them and this even though it sounds like it's the jetsons We think we're going to be testing this next year in our first patients Project two dr Sean Wang is an engineer and he's using these tiny magnetic nanoparticles to capture circulating tumor cells in blood So wouldn't that be great instead of having to get a fine needle aspirate of your tumor Maybe we can just do a blood draw and measure if your tumor cells are there and what's happening to them Dr Sam gambir who's the chair of radiology here has a very interesting project where he has smart nanoparticles That use sound waves to image tumors and the way he describes it If you yell at these tumor if if you yell at these nanoparticles and they're in your tumor they yell back at you So he has these super sensitive Ways of detecting the sounds that these nanoparticles are making when we bounce sound waves at them So that's actually currently in clinical trials for prostate cancer So I hope I've given you a taste of ways we can use new technologies to make molecular changes to measure molecular changes In your tumors over time gave you examples of a profusion CT Oh, I didn't talk about rgd2 But that's looking at blood vessels as well the glutamate tracer and making nanoscale measurements from your blood We're incorporating these technologies into clinical trials here for kidney cancer And the goal is to develop biomarkers to personalize treatment So it takes a lot of collaborators to do this kind of work So I want to thank each of them and each of you for attending today any questions. I'm happy to answer them I hope I can Be unconfusing As opposed to the targeted therapies the immune therapies Are actually trying to get your immune cells to eat the cancer the targeted therapies might try to slow its growth or reverse its growth so if I have a Great response to an immune therapy you can assume man my cells are eating it real quick, right if I have a partial Well, they're not eating it quite fast enough. The tumor is growing faster than The the cells or if it's stable there's a balance, right? My immune cells are eating it the cancer is growing neither one's winning, right and so with that Assume that okay if you got a stable growth then add something in there to Try to make the tumor grow slower so Your cells can eat it faster. I mean is there that kind of logic to it? So I think the question might be asking is okay Sometimes we have stabilization sometimes we actually have a partial response But we what we want is a complete response. We want it to go completely away So are there strategies we can use to combine things like immunotherapy and other targeted therapies to get to the Complete response adding perhaps two partial responses. So there's a lot of combination therapies that are going out One is with you know the glutaminase inhibitor which is a brand new metabolic metabolic strategy There's combinations of different immune flags turning on and off the different flags There's combinations of the immune flags and the targets the blood vessels that are approved therapies A new approach is that we didn't even address yet But we have a clinical trial that puts an antibody with a chemo and it brings the chemo directly to your tumors We have that in kidney cancer So that we have a lot of strategies to try and get to the complete responses because that's what we want I mean, yeah, it's great to have stable disease and and not have any effects from your tumor and control it for a while But we want it gone So these are these are some of the strategies that we have and then building in ways to figure out if it's working early And if not, why not that's a key piece. We're trying to answer as well Can these sorts of approaches or technologies be used to To evaluate like off-label Yeah to evaluate off-label use So, um, so if we're just getting a blood draw and trying to analyze cells We could so I guess let me take a step back So one thing that we do do is we do do mutation testing to see if there's any targets that are special to your tumor that We have drugs for that might be approved for breast cancer For example, if you have a breast cancer gene that's that's gone up or approved in a melanoma that we don't have And so first we can look for mutations and then those drugs would be off-label for kidney cancer So if we were able to get those drugs off-label Then and and want to know if they're working then right now the standard scan is a CT scan to find out But we would certainly want to apply anything that we're developing for the approved drugs To be able to make the measurements, too You want to look and see if that mutation that you have if we're turning it off or not That's exactly what we want to be able to do. So I'd love to be able to apply this and that's the goal Okay, thank you so much Alice. Thank you so much