 This afternoon, I want to talk just briefly on the role of immunotherapy and the area of targeted therapies and There's really three Three initial points to make the first is that Immunotherapy is the only established cure for patients with stage 4 Kidney cancer. It's a well documented now that the small number of patients that do get complete remissions on Interlaken-2 therapy may survive decades with no recurrence Second point is that many more patients will be helped with targeted therapies and immunotherapy whether targeted therapies See response rates and improvements in 60 to 80 percent of patients the number of percentage of patients that Respond to interlaken-2 is much smaller in the range of 20 or 30 percent even even in a well Picked group Third point is that as attractive as combining immunotherapy with targeted therapies is on a theoretical level There's mostly insufficient data About doing that and there's no established regimen that combines Targeted therapy and immunotherapy So let's go to interlaken-2. It was the name comes because it's a hormone Really, it's a peptide that's made by your white cells to keep for one group of white cells to communicate with another group of white cells it is Made in large quantities through recombinant DNA technology and given as a drug and it causes intense inflammation throughout the body and activation of Lymphocytes it was the first approved immunotherapy for any advanced human cancer BCG was proved about the same time for Prevention of recurrence of low-grade bladder cancer and Alpha interferon was approved for adjuvant use in Melanoma but for a Metastatic disease This was the first approved immunotherapy It gives durable complete remissions Published figures is about six to ten percent of patients There's a quite a bit of toxicity patients have to be in the ICU for a week then your home resting for a week then your back the ICU for another week and The patients that respond usually get that twice more for a total of six hospitalizations there was a lot of research done in the 90s Trying to look and see if you could give low dose and it'll come to and get the same sort of responses You can't really no long-term survivors of the other studies using low-dose regimens Some which actually the data Chiron never actually published. They were so it was so poor The regimens were so limited efficacy So it boils down to that over the last two decades. There's been limited physician acceptance and experience with it Here's a list of all the toxicities you have Mortalities can be one to two percent of patients overall and So it boils down the only very healthy patients can withstand the therapy. It's not recommended for patients over age We used to say 60, but I would really say 55 But the allure is that patients can Have durable remissions and This line let's see the this takes the the patients This isn't a hundred percent of the patients. This is the 20 percent of the patients that have a response Half those patients will relapse but the interesting thing is that if They survive 30 months from when you started therapy very few ever relapse after that and Here's the survival curve and there's definitely flattening off the survival curve. This is 10 years out And some of those some of the patient deaths are due to other causes at that point So as I said, there's there's been an evolution in terms of what patients are best to be selected You have to be physically feeling well have to be young The Kidney cancer about 80 percent of patients will have what's known as clear cell Histology when you look at the tumor and the microscope if the patients have what's known as papillary features They will have a lower incidence of mutations in the bond hippo Lindell Gene they have may have other different mutations and have a lower response rate And are not suitable for a high-dose interlucent to we found that Patients where the metastases are limited to only lungs or only bones also have much better chance of getting durable remission and patients that have lymph node metastases or Liver metastases and of course they shouldn't have other medical problems The other thing I'd like to say is is it's looking like also if interlucent 2 is going to be used Should be used as a first-line therapy Doesn't seem to be as effective if patients have had targeted therapy already So let's talk a minute about the attempts in the past of combining immunotherapy and targeted therapy The initial trials that led to the approval of bevacizumab or a vast in In renal cell cancer bevacizumab was given with interferon and that was compared to interferon alone in the combination with interferon with bevacizumab and Better response rate better survival so bevacizumab was FDA approved But we really don't know is how much that interferon which was given in moderate doses Really adds to the efficacy of bevacizumab alone And as far as I know Sandy, do you know of any studies ever they haven't looked at that directly? Have they no? Yeah, bevacimab Yeah so frequently Physicians recommend bevacizumab alone because there's much less toxicity than if you add in interferon There were trials trying to add to the number Tim cyrolymus to interfere on that showed no benefit There was one phase two trial reported in 2007 That showed that if a bevacizumab is given along with high dose interlucent 2 the response rates increased and performance progression-free survival has increased from four to nine months. I can still remember in 2003 when that trial was announced To really an audience of about a hundred oncologists and And we were hoping for a phase three trial that would really maybe demonstrate that Targeted therapy could be added to high dose interlucent 2 and get better improvement And when they announced it was going to be a phase 2 trial of only Small number of patients. They were sort of a collective groan because I think we all knew that it would be a long time before we could really incorporate interlucent 2 with targeted therapy The other things trimulimumab, which is similar to ipulimumab was tried with Sunitinib and there was excessive toxicity So I'm going to talk a minute about this is a short list It's not a comprehensive list of the things that are available as experimental immunotherapy the first two are Antibodies that are directed against proteins on the surface of lymphocytes. They're called checkpoint inhibitors. They Sort of release the break on your immune system a third one. IMA 901 is a peptide vaccine AGS-003, which I'll talk at more length is a personalized Dendritic cell vaccine which uses both combines both elements of RNA from the patient's tumor with white cells From the from the patient's bloodstream now tumulimab is a tumor targeted super antigen There's also an anti PD-L1 antibody which works similar to the anti PD-1 antibodies There's several other Immune stimulants that are in trials So the rationale for Immunotherapy and metastatic renal cell cancer rests on the fact that we know that the immune system is Disregulated and weak in metastatic renal cell cancer there's increase in certain suppressor cells and we've learned in the last Two decades a lot about the Regulation of the immune system due to both positive and negative regulatory signals that Affect your white cells and your immune response to the tumor and we have available now therapeutic agents That are helpful We know that from other malignancies immune modulators immune Inhibitors are effective if it be limo map was FDA approved in 2011 in melanoma because Really now two phase three studies demonstrate improvement in overall survival And really those are the first phase three studies ever done in melanoma They ever showed any drug to have improvement on overall survival DTIC and interlucent two had previously been approved for melanoma, but they had never had Randomized phase three studies the other immunotherapy that was recently approved is a dendritic based vaccine for advanced prostate cancer so if it limo map Is a monoclonal antibody that attaches to the CTA for protein and The CTA for protein is sort of a break on your T cells So it removes the break and got approved in melanoma Now I was unable to really find a phase two trial a phase one trial in kidney cancer There were six responses and for 40 patients 15% so that looked somewhat promising But I think the phase two data so far BMS Bristol Myers has not chosen to go through to a phase three trial So it may have some beneficial effect in kidney cancer Let's talk a little bit more about how these checkpoint inhibitors work This cartoon shows the antigen presenting cell Which is presenting that little blue antigen to the to your immune system your T cell and When that binds together to with these other two Proteins binding the T cell gets up both the first signal and a second signal and that will stimulate that that Leads the stimulation of the T cell They'll proliferate multiply traffic to the tumor site and hopefully kill the tumor now Unfortunately, one of the things that happens is that the tumor cell may make something Or the antigen presenting cell may have something called the PD ligand and if that binds to your PD one then the The program death pathway Suppresses your activated T cells and promotes tolerance PD is it stands for program death. So if that that receptor gets active It gives a negative signal to the inside the T The T cell and the T cell starts to get exhausted may die so However Did I get forward? Okay So what's happening here is you have the T cell priming After the T cells prime the T cell travels to where the tumor is inflammation and other factors increased PDL one may be made by the tumor and Even though kidney cancer cells don't usually have even though kidney cells don't usually have PDL one on their surface Kidney cancer cells may have PDL one on their surface and that interacts with the receptor there on the T cell to suppress the effect of the of the T cell and the T cell becomes exhausted may die and In the renal cell cancer the PD expression is associated with adverse features including more aggressive disease and in shorter survival however similar to using epilimum map to block CTLA for the NIPD one antibody binds to PD one receptor on the T cell prevents it from interacting with This the PD ligand and so the T cell just gets positive signals. It doesn't get any negative signals and so That prevents Then the that the tumor cell that's that's trying to suppress the T cell it prevents that from happening and So over here these T cells are protected by the y-shaped antibody that's keeping that tumor cell From Downregulating the lymphocytes so the lymphocytes now start to proliferate migrate Produce cytokines like amine interferon that then can cause lysis and tumor cell death So let's take a look at how this works out with the clinical trials This is a harder to see diagram of what we just went through and it It was tried this one and a PD one which is the BMS 93 6558 now known as the volume map Was tried at two different doses one milligram per kilogram and 10 milligram per kilogram and the response rate was really pretty good 28% and 31% median duration of response was also pretty good 13 months And that compares quite favorably to interlooking to or the or the limited date on epilimum map Also, what we'd call a serious adverse effects. We're only seen in 21% patients And it didn't seem to be any worse than renal cell cancer patients and other patients in the trial getting melanoma or lung cancer so this graph It shows The changes in total tumor size and patients getting With renal cell cancer getting the volume may have at one milligram per kilogram some patients had tumors that just kept on growing Other patients had tumors that shrank if they're below the 30% line then they're qualified as a partial response this patient had complete disappearance of his tumor actually happened quite rapidly within big effect within What would that be nine weeks and Everything gone by 24 weeks and interestingly there was one or two cases this case here. There's actually a Some growth tumor growth in a new legion and then the patient later responded so sometimes with immune therapies you can see Swelling of the tumors or tumors new tumors seem to appear Even though the patient goes on to get a response And here's a similar graph to at the 10 milligrams per kilogram a Seem to have a little bit higher activity Little bit greater proportion of patients and you also see that these these these responses of a long duration You're out here at two years and that was sort of the cutoff for the study The patient longest patients had been followed for or two years and there's their cancer is this for patients their cancer is still in remission and Actually, they settled on three milligrams per kilogram is there those to go forward and this is CT scan very large tumor Inside the abdomen going out to the muscles that and by six months. It's it's almost all gone away So there's the initial results showed a correlation that if you if the tumor They stain the tumor and the brown is a stain that's positive for the PD ligand one and In this series the patients that didn't have any of this brown staining that the tumors weren't making the PD L1 none of them the 17 responded whereas If they had a PD ligand there was about almost a 50% response And but this was samples was actually a combination of a bunch of different tumors It's now in larger series. We're seeing that the response rate if your tumor doesn't make PD L Ligan is is lower, but it's still worthwhile So it's it's somewhat predictive, but not completely and we really don't completely understand the mechanism by which If your tumors not making PD L1 why that anybody would work, but it does So because of the promise of this antibody it actually sort of Went straight from phase one trial the phase three trial in renal cell cancer They never they didn't do a large phase two trial. They didn't need to it's working too well So this trial is open at Stanford. It's for patients that have already had treatment first-line treatment with soon it and then or some other TKI and They're randomized to do-do-do Either the the volume map antibody three milligrams per kilogram every two weeks or The mTOR inhibitor that was FDA approved a couple years ago. Everolimus at ten milligrams a Q-day And I know one patient the room that's had this went on this treatment But he's also the only patient in the world that ever got anaphylactic shock with his first dose of normal volume map Now we also there's also in trials of Vaccines For the treatment of metastatic renal cell cancer and I'll talk a little bit more detail about the ADAPT trial That's for newly diagnosed patients where they're randomized between Sunit and M a TKI and Sunit and M with the vaccine now this vaccine is is Really a pretty sophisticated product. It's there's four different key elements It captures all the antigens including mutated antigens. It works by expanding memory T cells Helps overcome it tumor-induced immunosuppression and we pretty well have a demonstrated mechanism of action And they can show that the patients that have a stronger immune response that correlates with survival So this is a little bit hard to see and I apologize for that So the patient has their The trial is aimed at stage 4 kidney cancer patients when their first diagnosis of having stage 4 disease and It's very common in patients with stage 4 disease one of Initial therapeutic maneuvers is removal of the kidney of the kidney That has a tumor in it There was a controlled trial With patients that were getting treated with interferon where a group that didn't have their kidney removed It's compared to a group that did have their kidney removed and in that era Which was what our treatment was a decade ago. Survival is actually better if the kidney was taken out So that's why frequently in patients with stage 4 kidney cancer. We advise taking the kidney out Before proceeding with further therapy So in this trial to make the vaccine some of the tumor Is taken at the time of surgery and it's shipped to a centralized manufacturing facility overnight There they separate out the isolate the tumor RNA and They amplify it chemically and They store that and then a couple weeks later after patients recovered from surgery The patient has leukophoresis Which is just a similar process to like donating a playlist of the blood bank You're hooked up to a free system machine for a couple hours, but instead of separating off your platelets They separate off some of your white cells. So those are also then shipped They separate out from the total white cells the monocytes and then they add some chemicals to the monocytes the monocytes become matured dendritic cells and And the they electrically Get the RNA to go inside those dendritic cells and then you have a mature Dendritic cell that is going to make on its surface the proteins that the tumor was making and so that serves as your vaccine Dendritic cells when you get when you get a tetanus shot in your arm First thing that happens is the dendritic cells under your skin and subcutaneous tissues go and take up that tetanus tox protein Texas Tetanus toxoid protein then go to the lymph node to teach the lymph nodes How to make an immune response to tetanus so this is sort of doing the same thing You've got your dendritic cells that are making your tumor antigen because they have tumor DNA inside them So they they have to make it up and they freeze the vaccine and so you've got enough enough treatment for a year So they did have did do a phase two trial here and what they did was Using these criteria you can separate stage four kidney cancer patients into ones They're going to do pretty well living 44 months group that's going to do intermediate living 21 months in a group that's going to do poorly eight months and They Think I can't really see this but anyhow treatment phase included Giving this for five doses every two weeks and what they found was that whereas if they took historical controls Using patients two-thirds intermediate risk one-third high risk that what they would expect in terms of Survival be 15 months in this phase two trial of a small number of patients Only 21 patients, but it was impressive because the average survival those 21 patients was 30 months So that's longer than what that would be expected and the patients that Had A long survival also showed this shows the number of The increase in the memory T cells Between when they started treatment and after the fifth dose of this vaccine And you can see it increases the memory T cells and the patients that have increased memory T cells live longer So Now we have the the trial that was started last year patients Pre-treatment get Diagnosed sign-in-form consent rule a kidney get registered and they are randomized two to one 67% of patients will get Sunit nip standard treatment along with the vaccine the other third will get just a Sunit nip alone and they don't need to have the leukophoresis and They're planning to compare these two groups for survival And it's going to take a few years before we see the results And I think I've really gone over all this it's a it's open label They're collecting a collect tumor from about 700 patients hope to get 450 randomized There's no placebo control patients that gets in it and they don't have to undergo leukophoresis and And These are eligibility you have to have clear cell cancer Patients should be ones that you want to do an effect to me on Patients should be patients there where a Sunit nip is initial therapy would be appropriate and They need some tumor we can measure because they're looking not only at Long-term survival, but also whether adding the vaccine to Sunit nip speeds up tumor shrinkage So the dosing continues And if patients start to have some progression on the Sunit nip they may continue still to receiving the Vaccine even if they're switched to a different therapy And It's expected that they'll do it in 42 months. Let me see So this is an incomplete list of the trials of immunotherapy that are available One trial open at city hope Uses PD1 antibody the volume Mab in combination with either one of two targeted agents or with epilimum Mab I have one patient that just got on the combination He's doing reasonably well There's an IP one antibody along with a dendritic cell vaccine There's the Argos trial. I just mentioned the nipd one the volume Mab versus the everolimus. It's a van opens in Stanford And there's a nipd one ligand antibody That's also open. I'm not sure if there's any West Coast sites for that and you have a CD 127 antibody That works a little bit. It's more Activator of the immune system and not one that blocks the checkpoints so For the moment Immunotherapy of renal cell cancer is partially eclipsed by targeted therapy, but I think the future is Future is going to be bright. We're going to see in the next few years some agents that are a lot More effective than you're looking to a lot easier to take And I want to thank all the people that actually made all these slides for me a Time for questions now sure. Yeah, each Each monoclonal antibody has its own unique protein structure So an allergic reaction to one would not necessarily predict an allergic reaction to other ones Now the the incidents of Because I've done a lot of research with the epilimum ab the The antibodies epilimum ab and the volume ab have a low incidence of allergic reactions because The mice they use to generate these actually had human immunoglobulin genes So that some monoclonal antibodies are sort of part mouse and part human But these epilimum ab and the volume ab are actually entirely human so that it's you know allergic reactions are pretty rare and There must be some Probably cross reactivity to the variable portion of the antibody that's the part that's actually doing the binding to CTA for and That part of the antibody would not be the same in a in a different antibody Wouldn't you agree with that Sandy? Yeah Yeah, I mean we've given over a thousand infusions epilimum ab and we haven't had a single allergic reaction acutely Yeah Let's see. No No, no, I don't think so you mean the one was one milligram and ten milligrams No, I think that those those as far as I know those were completely unselected Yeah, yeah Yeah, it was unselected phase one study So that's yeah, and then when you go back and pull out the ones that were positive for PDL one There's one for sponsorates even higher than that It's like more than a 40 to 50 percent range Now and the what well what I know of that is is actually melanoma data and It doesn't seem whether you take the cutoff being 20 percent cells 5 percent cells 1 percent cells showing it It doesn't seem to matter too much where you cut it off. It's it's a somewhat of a predictor, but not a perfect predictor And contrary to that that slide I put up that showed zero out of 17 Which you know if you had zero out of 200 you would say well That's that's a excellent negative predictor, but it's not turning out that way at least no, no I Don't Really have exact figure No, it'd be and probably 10 to 20 Yeah There are long-term dangers, let's see. I mean I've had one patient that had a heart attack He survived it, but you know, he's on cardiac. Yeah, right during the treatment or the peak of treatment The People can lose weight And I had one patient that she had some pre-existing neurological Outer male there MRI and unfortunately she had an HMO So I never got a neuro consult before I treated her and she went to coma for 10 days and A month later her she's pretty well back to baseline mentally, but I actually don't have long-term follow-up on her mental status That would be she was sort of an outlier and probably had something Weird going on in her brain to begin with because it wasn't normal on MRI In general, you know everything goes back to normal You know some of the long-term side effects of chemotherapy, for example, there's a Take enough chemotherapy. There's the incidence of acute leukemia goes up, especially if you're on chemo for over six months That doesn't happen because interleukin-2 is a really a normal protein your own body makes So it There's there's really not not I haven't seen too much date on on long-term side effects I'm certainly you can you know, like I said a heart attack it's I Haven't had any patients that have had a stroke, but if your blood pressure is low and you have Compromise cerebral blood vessels certainly one would could have a stroke