Immuno-Oncology: A Future Look

morning if everyone could take a seat we're gonna get started last chance to get a coffee tea before we we kick sorry so good morning and welcome to our inaugural see our eyes look into the future of amino oncology my name is Andrew sy and I'm the co-chair of the board of trustees for CRI and I want to thank all of you for being here today to make this a complete IO ecosystem in the audience we have healthcare investors we have the media and we have expert panelists from both academia and industry in my day job I'm also an investor and I'm really excited to be in the audience today to listen to what the world's leading experts have to say about the likely evolution of the io landscape so first and foremost you know as a human being which we all are we've all been touched by cancer and and certainly it's what brought me to CRI I lost my mom to cancer when I was a kid I've had a couple battles with cancer myself and so there's a real personal deep connection for me this this this this submission and it's the main reason that CRI is the main focus from my philanthropic philanthropic time and resources and why I'm gonna continue to do so until all cancer types have been addressed so let me tell you a little bit more about my experience of CRI and what blew me away to join their cause seven years ago so CRI was started 65 years ago on a view that harnessing the immune system could be the ultimate cure for cancer now for the first 55 years or so there wasn't much proof of this and what's amazing about this organization is that they persisted and believed well have well ahead of the evidence so in the audience how many investors here today can take a fifty year view a 50 year bet it's amazing not many people can do that so CRI has always been focused on primary research and was the pioneer and for decades really the only game in town for funding grants leading scientists around the world that wanted to test their theories on immunotherapy even our CEO Jill Oh Donald Torme is a scientist herself and this speaks to a complete obsession with being a scientific organization this focus on primary research is the reason our scientific advisory board many of which you're you'll listen to today are really the who's who of the space these are new relationships but long-standing partnerships that go way back to time when IO was really this this fringe thing now today IO is beefing additional ecri has made collaboration a cornerstone of their philosophy by bringing together academia and even competing Pharma groups to work together we are the the UN are Switzerland so to speak of immunotherapy and our clinical accelerator is a great example of bringing different parties together in the pursuit of saving lives there have been some amazing breakthroughs as a result of these collaborations if you look at the picture here there's a picture of Sharon Belvin so 12 years ago she was diagnosed with stage 4 melanoma and tried all types of treatments unsuccessfully and then she signed up for a clinical trial at sloan-kettering with Jed wolchuck and it was testing an immunotherapy that was created by Jim Allison she had complete response she's been cancer-free ever since and it's absolutely incredible at what's possible so even though we've come from believing ahead of the evidence to actual evidence this is just the beginning we need more stories like Sharon to protect our families and our loved ones from all types of cancer today's gonna be discussion about what needs to be done to address all cancer forms using immuno oncology so if you look at the agenda today Jill's gonna kick off with a deeper understanding of CRI and what we are doing to continue our leadership in the i/o field then she's going to moderate a panel with our with members of our scientific advisory board including Jim Allison you recently won a small award didn't Sweden I think first lies to work as well as two other legends in the space Phil Greenberg and Bob von der Heide we're gonna have a Q&A session so hold questions for the Q&A we're definitely gonna get involved and feel free to ask anything you want and we're gonna have a short coffee break afterwards we're gonna have an industry fireside chat moderated by CNBC's Meg Terrell and conclude Jorge and Coppola super general and ani Virgil of BMS have another Q&A session where you can ask more questions and then finally we're gonna close with an announcement of CR eyes most recent star grant recipients and these these folks are really the future of CRM you know ecology and so remember their names because you'll be reading about them in the not-too-distant future and then it noon we're gonna have lunch encourage everyone to stay to go to mix and mingle with with all these leading experts in the space I'm also happy to talk to anyone who wants to get involved in CRI in any smaller big way and kind of share my experiences on what it means to be a trustee at this great organization and so we have a full packed day with a great lineup of speakers and without further ado let me introduce Jill O'Donnell Torme the CEO CRI well it's my pleasure to be here and as we know today's discussion is about the future look at the i/o space but I thought it would be important to set the stage first and see where we are actually today I don't know if everyone knows about this but CRI has developed the first in-depth quantification of the i/o landscape and this is a capability that CRI uses to guide us to use our philanthropic dollars in our clinical strategy but it's also a resource that's available and I think valuable to the entire field so this is just a slice of our i/o landscape which really just shows PD 1 or PDL 1 combination trials and the growth that we've seen since 2017 to 2019 there's been an 86% increase and this is no surprise everyone knows that there's a credible increase the number of immunotherapy clinical trials but this is a quantification of it and obviously this would also been a 79% increase in the targets that these combination trials are looking to combine with with PD 101 so we've done more recently just reported and published in May another look and this was a slice looking at cell therapies and in this most recent and now it certainly shows that from 1993 to 2019 there's been a real explosion in cell therapy clinical trials in fact in that period of time there's over 1200 initiated and obviously in the past decade you really can see the growth has significantly increased year after year and you probably can't see all the different types but the light blue color there is signifies the car T cells so if obviously car T cell therapies are dominating the space with cd19 as the most popular market target so obviously immunotherapy is changing the landscape it's changing how cancer is being treated and it's certainly true that you can see that right now there are 19 approved immunotherapies by the FDA in the six categories that we use in our landscape and that's covering over 20 different cancer indications but how did we get here well I'd like to think the Cancer Research Institute had something to do with this we were founded in 1953 by Helen Coley noughts who was the daughter of dr. William B Coley who was considered the father of cancer immunotherapy CRI was obviously a pioneer and we were always singularly focused on immunotherapy decades before the current wave of excitement enthusiasm so I am very proud that CR eyes long term dedication in support of immunology and tumor immunology has played a significant role in laying the foundation for where we are today and I now believe that certainly the entire scientific and medical community would all agree that the immune system plays a role in and able to play a role in the treatment control and potentially cure of cancer but this was certainly not the case to even 10 years ago but CRI stayed the course and we're now reaping the benefits of that persistent vision but as we know the majority of cancer patients are still not yet benefiting from the immunotherapy and there's a great deal of work to be done before we realize its true potential so CRI is going to remain committed to the mission that we've always had we believe obviously that the support the support of basic and translational research is critical and that this will be yield really yield is from this that we get the basic discoveries that will really yield the impact for the entire field our unique clinical strategy is really a collaborative model that's really helping to inform and de-risk immune based combination therapies and accelerate development we also have ability to convene the world's leaders in the immunotherapy space and this really helps position us as a global thought leader and more recently while we still remain primarily a scientifically focused research organization we have recently taken on the role of being a trusted third party to cancer and their cancer patients and their caregivers as immunotherapies have moved into standard of care now our biggest asset I would say for the Cancer Research Institute is our scientific advisory council and these are the people that really guide all our programmatic decisions and recommend the people and the projects that we should support these are led by Jim Allison who's the director of the scientific advisory council along with these five associate directors all who I'm sure are not strangers to this audience the SA C includes fo but four Nobel laureates with Jim being the latest one and actually 24 members of their National Academy of Science so we continue at CRI to fund the entire spectrum of research from the lab through the clinic and we do this here this just is showing our major research programs our Irvington postdoctoral fellowship programs is the way that we are really supporting and training the next generation of cancer immunologist and these are the people that are doing a lot of the basic laboratory discoveries our clinical laboratory integration program is a translational program that's really more focused on projects that are taking these basic discoveries and applying them into developing new immunotherapies our clinical strategy is called the Anna Maria Kellen clinical investigator and I as I said it's a unique collaborative model which I'm going to talk about a little more later on more recently we've added two new programs our technology impact award this is the first time that CRI is supporting not biomedical research but rather recognizing that it is advancements in technology that really underpinned the ability to take major leaps forward so these are seed grants that we're giving to cutting-edge new technologies that we hope will end up being applied and adopted by the the entire field at large and then most recently we've started the Lloyd J olds Star program Lloyd Jay old was our longtime director of our scientific advisory council before Jim and we have named these as scientists taking risks and will your get to introduce our first class at the end of today and we're very excited about this as support for mid-career scientists so I think it's important to give it a little bit more detail about what see our eyes funding has has happened over the last six decades and we look at this over kind of decade by decades you certainly see trends in what we're supported and what has been really important as the foundational discoveries from where we are today so from the 50s to the 60s there is really about looking at Coley's toxins and trying to see if we could confirm why what what Coley had originally seen in the 1890s so it was a lot about nonspecific immune stimulants and and the hint that perhaps Coley's toxins worked through an immune function it was really in the 1970s with Lloyd old guiding us and he used to always tell Helen and I knew Helen back in the day that science really needed to catch up to her father so it was really Lloyd who puts Eri on the path of being truly dedicated to immunology and so in the 1970s there was really about really basic immunology understanding the components and how the immune system really worked and it really wasn't yet applying it to cancer in the 80s I think a lot of the focus was around t-cells I think we came to understand how important they were what they see how they see antigen prices antigen processing and presentation was a great deal of the kind of our portfolio of what we support supporting in the 90s we finally started moving a little bit in away from basic immunology and doing a little bit more cancer immunology but never leaving the basics and really trying to understand what are the targets what are the potential cancer specific antigens so antigen identification was a big part of the portfolio then and it was only in the 2000s when I really felt our scientific advisory council felt there was enough understanding about the immune system and how it really applied to the cancer question that we could really start supporting more clinically relevant cancer immunology and a lot of this was focused on developing therapeutic cancer vaccines but at the same time recognizing how important the immuno suppression that takes place that the tumor site is and how can we overcome that and now in in the this decade I I think it's all come together it was during this time that we've actually seen the first clinical successes of active immunotherapies and and our long-held belief that the immune system could be used as a way to treat cancer was really validated so CRI did get it right but continued support the research that gets us to the next level so one of the things we're doing and I wanted to talk about this is our clinical accelerator and this is a collaborative model that serves as an incubator to study promising immunotherapy combination trials and we work with a network of about 90 clinician scientists couples with our IO landscape and together this helps us to define the most pressing clinical questions and identify and prioritize innovative research driven clinical trials that of novel combinations that can address these questions we then negotiate access to import the drugs that we think need to be brought together to be combined for the biotech and pharma we get access to their pipelines and we also negotiate agreements with them on financial returns so that any drugs tested in the clinical accelerator if they reached certain milestones in clinical in successful commercial advancement we get some returns and this is comes back to our venture philanthropy model we then partner with other not-for-profits to really be able to carry out and execute these multicenter clinical trials and all of the trials actually have exists a good deal of funding for deep correlative analysis of what is happening at the in the patients so that we can learn as much as we can from every one of these patients now since 2013 we have invested over 110 million dollars into this clinical accelerator model that has supported 15 trials two of them platform studies and I think moving forward we're seeing platform studies are the way to be most efficient and effective of using our philanthropic dollars to have impact over 600 patients have been treated in 23 different cancer types and we've obviously partnered with a variety of companies and not-for-profits and our primary not-for-profit collaborators are the Ludwick Cancer Research Parker Institute for cancer immunotherapy in the Canadian clinical trials group and this is just a list of the current for-profit companies that were actually in the convening negotiating in contract with right now and working without the trials that we're doing wanna take one minute just to explain one trial that I think exemplifies the power of this model under kind of a not for profit an umbrella this is the print study that was done in collaboration with the Parker Institute and it's a trial that was for metastatic prostate cancer and it actually tested for drugs to standard of care chemo therapies along with two immunotherapies one and a cd4 T agonist and the other an anti pd-1 antibody nivolumab and I think this shows you that amazing speed that's that from the concept which was back in November of 2016 agreement sign and ion IND submission in six months which is a pretty amazing feat to accomplish first study trial site was initiated in July this study had seven different sites was led by dr. Bob von der Heide who you'll hear from later and we were able to just recently in March presented a ACR the initial results from the first 24 patients in the study it's looking like it has at those 24 patients have been very tantalizing exciting data that looks like the response rate is better than what was seen in just chemotherapy alone since March we have fully accrued this Phase two of this study with another about 70 something patients and we will anxiously be awaiting this year the analysis of the rest of those and keeping our fingers crossed that the initial data will be carried out with this larger number so this is exciting it's great news for the pancreatic cancer patients and I think it just shows you the power of our clinical accelerator model so in preparation for this where do we go from here and I think prior to this meeting we actually surveyed a hundred CRI scientists these are members of our scientific advisory council scientists that were funding to get their viewpoint of what is coming down the pike and which of the important things in terms of near-term no surprise here I think one of the major issues is how to return coal tumors into hot tumors how do we optimize they checkpoint blockades that are fda-approved at this point and how do we move cell therapies into the solid tumor space a little further on I think this clearly there's going to be efforts beyond just the checkpoints that we have today there's a lot of work looking at trying to being more personalized and ident fiying neo antigen predictions and using those to develop maybe off-the-shelf or personalized medications and obviously we need to look really closely it's what's happening at the tumor site the tumor microenvironment the stroma genomics and epigenomics play a big role and obviously metabolomics and the microbiome so all areas of active research which i think will really inform and probably lead to the next generation of immunotherapies and of course big leaps i think there's still questions though the scientists felt that what is is Ken artificial intelligence be used to deal with this the big data that's being generated at this point is machine learning a possibility can we develop models that are non animal based models that may be better predictors of what's going to happen in clinical trials and obviously technology but underlying it all I think in all of these cases we heard over and over again but we can't protect the basics though we're doing all this work in the clinic it really means we still have to come back to the lab there's still a great deal to discover about how the immune system functions and works and interacts with cancer so for that reason it really fuels us and we will be using this fret CRI to really guide where we're going and I think we'll touch on these topics in the in the panel discussion coming up so I just want to close and saying how you could help us obviously we're an organization that relies on philanthropic investment from individuals foundations and corporations I'm always happy to get checked so if anybody wants to support us I'm here you can find me anywhere obviously we also have our i/o landscape it's something that I think is useful perhaps to you and your clients and we can do customized io landscapes so please reach out to us and there are other engagement opportunities we're always looking for new trustees we have an associate board which is for kind of the younger generation that we're grooming to become full-time toasters and also obviously corporate partners so with that I'd like to invite our panelists up okay you guys can come on up we have Jim Allison who from University of Texas MD Anderson Phil Greenberg from Fred hutch in the University of Washington and Bob Vonda Hyde from the University of Pennsylvania order okay keep us straight four people standing there's seats over here oh and there are seats yes you don't have to stand it's good we're gonna be here for a while so thanks I think maybe we'll start off by each of you maybe just introducing yourself and it's telling you the areas of interest that you and these are all members of our scientific advisory council so these are the guys that I've known for years and years and years that have really helped move CRI forward so Jim why don't you join Jim Alstom with Pam Shauna run the cancer immunotherapy platform at MD Anderson and my especially or was that developed and I see today for began the development of seats like four and continued to do both Mouse work and participate in some design of clinical trials to look at combinations and try to improve the efficacy and understand why their failures and come up with a rationale for moving in a you know you know logical and science-based matters that raised the response rate I'm Phil Greenberg I'm at the Fred hutch and University of Washington in Seattle our lab has been involved in trying to manipulate t-cell responses to target tumors a lot of this was originally done with cell manipulation and and developing techniques for expanding cells outside the body and then giving them back to create effective immune responses in the last 15 years really it's become more about synthetic biology and genetic engineering so we are now engineering T cells outside the body and then giving them back to patients trying to create immune responses that the patients can't themselves generate but that you can now make an immune response better than a patient could otherwise generate and create effective responses for cancer okay thanks Jill my name is bob von der Heide I'm at the University of Pennsylvania I'm the director of the Abramson Cancer Center they're relatively new job for me I've done it for two have been a pen though for twenty years I think I met you upon my arrival at Penn thinking about the CRI many thanks to the CRI as you described you were in it before it was hot right speaking of cold too hot you knew it was hot all along I bring the perspective of a cancer immunologist immunotherapies to my role as director of the Cancer Center it's a really an amazing time we've been pleased to be at the epicenter of what's going on I've been focusing our laboratory work on diseases where we haven't had much luck and certainly immunotherapy hasn't garnered an FDA indication yet and we focused down on pancreatic cancer as you heard the clinical trial I've been involved with with pancreatic cancer maybe we'll return to that so let's start kind of big picture will start on checkpoints obviously how does the area Jim you've opened up the field got the Nobel Prize for it so what do you think are the biggest challenges immediately ahead of us in terms of optimizing checkpoint treatment I think one of them is what Bob just mentioned this getting pancreatic cancer going to bless them on some of the other ones that have not responded well yet to respond I think that where I think that the field is beginning to settle around in checkpoints at least a core of at acetyl 4 plus at a PD one because of their unique and not overlapping properties that make them not a really great combination and two that with that that's cotton estamos 60% melanoma 60% of durable responses lasting you know five years for the combination probably is going to go out to ten or more given that the glue meant by itself has 10-year plus at about 20% of melanoma but anyway then we're gonna have to start adding additional checkpoints we've learned in the last few year there's there's there's a couple of dozen other molecules that have some promise there they're not all going to be you know getting changers but they can add a little bit I believe it we can but they're expressed in different kinds of tumors for learning and so it's gonna have to take a individualized basis of really looking you think biopsies to see what kind of things kinds of things are expressed in different kinds of tumors not watch cells then putting together a package that that makes sense and of course there's I did it adding it to radiation and chemo and things like that that are coming so Bob do you think checkpoints are going to be kind of the backbone of treatment going forward or there is there places where we're not going to use that one it's right now hard hard to imagine not having a checkpoint backbone because of the biology that Jim and many others have revealed but by themselves I think we're realizing the limitation of stacking checkpoints I totally agree with Jim about pd-1 and ctla-4 but as we continue to stack I think we'll see the rate of responses not increase as much as we want and we're thinking that one has to actually generate those t-cells in the first place by a variety of mechanisms and there's many many mechanisms that have been tried over 20 years and many of them fell out of favor and if you think about it they came on they came online when we didn't actually have ctla4 pt.1 so it's a little bit Back to the Future you know once you generated t-cell and you're asking it to destroy a tumor the problem of t-cell exhaustion the problem of optimally priming our power before us and we have great drugs for that now pd-1 and ctla4 so it's in the near future a checkpoint backbone is for non cellular therapy and even maybe for cellular cell therapy eventually is what we're looking at I think I know fill you more a cell therapist then check person so obviously great successes with cellular therapy and hematological malignancies I think you know obviously a big thing can they move to solid tumors and I guess I want to hear what you think needs to happen is for them to go to solid tumors and do you need checkpoints with silver so so I think I mean the advantage obviously with cell therapy is as Bob is alluding to as you generate the response so that rather than then try to activate something that then in some cases unfortunately is just not present you can essentially synthetically generate the response outside the body by having selected a target that the tumour does Express and give those cells back now I think in in the early phases of this we are doing it in the context of adding checkpoints but one of the real advantages in cell therapy is that you have the opportunity to genetically engineer the cell so that the checkpoint is it can already be excluded and so for example it's very easy to knock out PD one and so that you don't need to then provide a reagent that has potentially some systemic toxicity in terms of its it's blocking PD one on every cell in the body so you can engineer cells so that they now can function in an environment where they're getting those negative signals and an our lab and several other groups are now looking at ways actually to co-op some of these negative signals so for example we can take PD one we know that when a t-cell is being active in a tumor it stimulates unfortunately the tumor to upregulate the inhibitory ligand PDL one and drive a negative pathway into T cells so one simple thing is we could knock out that genetically knock out that pathway but we also can create synthetic receptors that for example have the PD one receptor on the outside but instead of having the inhibitory signal that PD one delivers we actually change the signaling pathway so that now it actually delivers a positive signal so that now when the T cell gets into the tumor instead of seeing PDL one is a negative checkpoint it actually sees it as a positive signal and so we can N and P d1 is just the beginning of that I mean we've reported are the ones already and other groups are looking at a panel of signals so I think synthetically we're going to be able to make T cells that really can work in the solid tumor environment and we're actually getting ready to start a trial also in pancreatic cancer targeting that and again it's the first generation is just the receptor the t-cell receptor the next generation are these synthetic biology approaches so I guess I'm a little bit biased I always when I think about solid tumors I'm always worried about the antigen obviously see day nineteen perfect antigen and hematological malignancies you can attack your b-cells it doesn't matter I don't think to date we have such an exquisitely sense the expressed target for solid tumors so can we get over that what did what you know I just think you know these are very powerful immunotherapy is off targeting you have a that antigen somewhere you didn't know it was you got major problems for a patient so what do you think on that so obviously I mean I think one of the real advantages now with the advances in molecular biology is you can you can look at a tumor and you can say what genes does this Express and how do those differ from from normal cells and so we've been able to identify several candidate targets I think what you're right about is that the we are probably going to need to target more than a single antigen for many of these tumors so you may need to put in T cells with two receptors in it or two different T cells one with each receptor in it I think what your what you said is correct I mean turns out that cd19 in a sense is a perfect target but it's perfect only because the fact that those T cells actually see normal b-cells doesn't impact the patient's survival so you can live without them the same is true with a target that's being looked at in myeloma now B CMA again it looks to be very effective but it's because you can live without your normal plasma cells that again you can get away with that for the solid tumors is not many tissues prostate and breast represent tissues were in fact you can essentially target a self antigen and because you can live without a prostate or a breast and so if that's the price of having an effective cancer therapy that's probably going to be considered an acceptable toxicity and pancreatic cancer we think we have found a target means Filan that can be can be targeted but there will likely be escape from that we've already seen that we have a study that's about to get published actually on Monday and in Nature Medicine targeting wt1 and leukemia but there is potential escape from that so we need and we had now looked at alternative targets that that may be ultimately necessary to build on those kinds of therapies alright so we obviously talked about overcoming to suppress in with checkpoints at two different spots but ctla-4 and PD wines we're talking about priming T cells in a vaccine maybe or or by bite cells but what about you know when we talk about turning cold tumors into hot that means you know the T cells are not infiltrating the the tumor bed so what are the current thinking and strategies of how do you get T cells to traffic how do you get them to infiltrate oh there what's the most exciting things there well one thing that we've shown that it's is that seat or itself can do that in prostate cancer and kidney cancer at least and maybe some other cancers for other ones that are that are harder though there there are ways coming up with chemokines or even a light dusting of radiation to activate the the vasculature and the tumor and allow extravasation of cells into it and there are a lot of more specific things coming along I think well you know we're we're impressed that a properly activated t cell can find its way into some of the most hostile tumor micro environments and if you have a poorly activated T cell or a dysfunctional T cell even if you take down all the barriers some of them physicals some of the metabolic some of them signaling mechanistic that T so we'll still have problems and so it was one of this ideas a hypothesis we had when we brought cd4 T agonist in to treating patients with pancreatic cancer where you know 90% of those tumors really are void of T cells and by activating those T cells with cd40 and some other agents and releasing some of the brakes with pd-1 clearly in the mouse we're able to deposit huge numbers of t-cells into an environment which is among the most hostile described yet for for cancer now can we do better sure can we get rid of the macrophages and all the other mediators absolutely but if you don't have a properly activated t-cell either in vitro or in vivo I think we're up against it pretty badly so t-cells are critical we know that now what let's talk about you know you're here about the micro environment you know you have MDS C's you've got b-cells yeah but what you know what's the latest thing that we in terms of our that do we need to target them doing it get to getting rid of them do we need to inhibit their suppressive activity and I guess also what role is something like an NK cell plays in relationship to a t-cell takers on that yeah well so I think I think we we are increasingly understanding how the the cells and the components and the tumor microenvironment impact a t-cell response whether it's one that we provide by cell therapy or we activate in vivo so there are many things now that I think will change whether a khole tumor will become a hot tumor and it's we've lived there are a pathways the beta-catenin pathway the tgf-beta production the CDKs now actually are also all there but we have reagents now that can target each of these pathways and we'll make these tumors essentially less hostile for an immune response so I think we will be able to do that and and I think as as bob is shown with anti cd4 T rather than for example necessarily get rid of some of these cells that are in the tumor microenvironment you can modify them so that rather than being anti a tumor an immune response you can actually recruit them to be part of a t-cell response and we actually showed in a paper that just came out and in pancreatic cancer for example that depleting macrophages is actually worse than then for example trying to activate them that you can actually croûte the merit the macrophages to be a potent anti-tumor effect or mechanism as opposed to getting rid of them because they the way they're there they're naturally they're interfering one thing I would I would add to that in we're talking about a lot about pancreatic cancer cells stick with it for a minute then the number one tumor micro-environment feature that is in the least in the mice the genetically engineered mice that's causing a cold tumor are the macrophages and you can deplete you can re-educate but what we've learned I think over the last couple of years is that they're there they're in their current state these macrophages because they're instructed by the tumor cell itself so when we talk about the tumor microenvironment T stands for tumor all right so let's not forget it and as a as a pancreas cell becomes mutant with K R s from that moment it begins a signature a gene expression pattern that brings in and poisons macrophages we can alter and and often that is caused by either genetic or epigenetic reasons for the tumor cell to secrete chemokines that bring in and mold macrophages in that way if you go up one stream and damage that pathway in the tumor cell or prevent those chemokines or cytokines and we've shown this now three different ways the macrophages go away and now the T cells come in sometimes without any additional impact and certainly you can now treat those tumors with immunotherapy very well so the tumor cell is instructing the microenvironment and it's probably different tumor tumor determined back to Jim's point where we need to have precision immuno oncology to know what is the what are those paths yeah so kind of going to like biomarkers I mean obviously we here we have all these fair complicated there's a rheostat I think you know it's positive negative it's not all or nothing you can you can modulate this and that how are we I mean obviously the goal wouldn't it be great when a person gets diagnosed with cancer they get the Jeannot Jeannot man out you know their tumor Illinois's they're personal they mean a lot what and being able to say what does this patient need for a personalized immune based therapy that's going to treat their cancer this requires biomarkers you know I mean biomarkers is kind of a buzzword everybody hears about it not so easy biomarkers are very different from targeted therapy biomarkers I think when the immune system you're dealing with a system there's multiple so are we going to get be able oh with a lot of work looking for biomarkers I'll be getting anywhere depends on what you mean by biomarkers and there's a sense of having some magic thing you can pick up a baseline that's gonna tell you whether they respond every that's not happened and it's not my mind not likely to happen and so but the different sort of biomarker that is just is the signature not only a single thing but the signature of what's going on the whole symphony you know the t-cells and the right kind of macrophages and the whole thing coming together well and one of the things that is really disappointing to me you showed there were 2,000 pd-1 plus something trials going on almost none of those are based on any kind of rational understanding of what the interaction between the two things would be and unfortunately if there's not a clinical signal nothing is learned because nobody looks for the biomarker nobody looks they're not taking biopsies from the patients that may be failure don't give a clinical signal to learn what was lacking I mean we've got a pretty good idea of what the overall successful response looks like and if you add something you know and you get partially there that's worth knowing and you could instruct the next thing you do but if you don't know that that biomarker in a sense then nothing obviously I'm gonna plug CRI in our trials we try to make sure we do these biopsies and blood and really analyze what's going on in and I think there's a movement for more of that happening but I guess you need big datasets yes oh yeah I don't think you do I don't think you need big datasets I think and oh that's what I'm talking I was just hints of where you are you know like we found it's in many instances looking at somewhere around a dozen to 20 samples and you could you see signs that tell you I mean it's not a p-value but it could be a signal that says hey this is the overall thing that you need to look at yeah I think I mean I'm I'm a bit on the other side with big datasets because I think it's really is is giving us a lot of clues about who respond and who won't respond and why and also we're learning why that is and you may be able to increase make make the switch from a non responder to a responder I think for example there was just a study published I think yesterday and in head and neck cancer an oral squamous carcinoma that showed that you can do with actually machine learning and artificial intelligence pull some of this these large data sets together and actually very accurately predict the what the five-year survival will be for that cohort I think the problem we have right now is that the biomarkers are very good at telling you the likelihood of response so as a physician in the clinic telling a patient that this is likely to work that's very comforting the problem is is that there's no biomarker that excludes a patient from responding yet and so that's that's the real difficulty so you can collect all this data and does that mean that you should say no you won't get this therapy that we're not that's where we're not right now and that's what we need to get because these therapies are unfortunately expensive and have some risks of toxicity so we need to really so and the more data sets I think we get the more information we collect we will ultimately I think be able to learn some of it what I think down the road that's true but now it's not you know you can't do it like prostate cancer just became a little student you started just simply based on looking at untreated it after treatment and seeing what was missing and then what's still missing and then yeah you can move from there there I think there we want this to be a reality and and we're far from it but I you mentioned you know we've done this before which was with targeted therapy right and those were precision oncology got its name and you know we're looking back to that experience to see how how was it successful and it involved technology which was brand new it involved doing those assays in a routine way in a CLIA certified way the assays were performed and sent out to clinicians before we understood every last mutation the the the results are examined at every major institution by a molecular tumor board which was a feed forward information back this begins to look like laboratory medicine and a lot less like my postdocs on Saturday morning and and we need to discover in that setting but to when we start ramping up in a throughput we will have high quality data that can then be analyzed in the way phil was talking about so I'm optimistic that we'll get there we're going to need different technologies it's not just it's not just DNA sequencing but it does include DNA sequencing and RNA sequencing and a taxi I mean those are some and we know how to use those technologies but we need multiplexed tissue analysis circulating tumor analysis cytokine and many other things all of which can become CLIA certified and I think that will avoid us from generating a bunch of bad data yeah so I switch switch gears here what about the microbiome you know we hear there's been studies that show that different people with different micro biomes react differently to to checkpoint blockades what do you think does it just it's real it's definitely real I we've been working with Jaguar goes well the pioneers in that and it's definitely real you know what where to take it not so sure yet there's some simple things that we have learned though there's a group at MD Anderson for example that learned how to do fecal transplants to actually fix patients that had that had seemingly you know colitis that was they couldn't fix any other way patients it was just refractory to any kind of I mean a suppressant do that but you give him a fecal transplant in 48 hours they're perfectly good that's it critical trials now but there's some interesting work that's coming out besides the idea of identifying one or a few bacteria that will be good and that's saying you know what effect things that people are doing now have are having and there's some data that's emerging that will be published soon I think showing that people that don't take you know just any old probiotic off the shelf you very often don't don't do so well because we don't know enough yet about how to predicted it so you've been trying to do this at home without this it's not a good idea you know I think I think that's a really important issue so there are trials I mean there are like the Bifidobacterium there are some bacteria that look like they are important for promoting a response I mean there and I think as Jim allude to there's a I think there's absolutely no question that the microbiome plays plays a role and whether you respond to an immunotherapy or not it even actually plays the role whether you respond to chemotherapy or not which i think has been an enormous surprise but but the data is very clear so the role of the microbiome in in responding to to cancer treatments is is unequivocal the problem is that we are in our in the infancy of trying to understand that and I think the scary data is as Jim was alluding to is that people based on that have been taking probiotics with the idea that that would make them better responders and the data actually showed it was the opposite that that the probiotics people were getting and essentially in these off-the-shelf health food stores was actually interfering with the response now that's that was itself quite surprising but it is telling us that you can't do this by trial and error this has to be essentially science science base then it has to be a really defined question that you're asking and trying to answer and okay so in terms of moving a little bit better models for research discovery drug testing you know I think know what Jim's gonna say we need to do a lot of small phase one studies get some signals before we go out but you know how useful our animal models I mean in terms of predicting do we need new models is it should we go directly to phase one with some you know basic dead without going through animal stuffs or you know what I don't see how we can go faceful without animal models I think they're absolutely necessary and will continue to be not mean everybody says well they don't exactly give you the details of what's gonna happen in humans because they're different that's true too but you know they certainly give can tell you the big picture you know the general things that you need and if you don't if you don't have something I mean people say you're gonna get all why can't you just do it tissue culture well you can't humming the immune system is too complicated for that you've got too many interacting components that we don't know how to do other any synthetic models that come close well I think you know the organoid cultures now where you can actually grow in three-dimensions tissue from a tumor is actually really you say mean it's been it looks like it's becoming increasingly useful now for studying the use of drugs particularly some of the targeted drugs it's just the problem is trying to and you can ask some questions about whether an immune response has the potential to be beneficial the problem is is you can't as Jim's alundra you can't really recreate a whole interactive immune system in a dish and so you'll get some insights but you'll also lack some information that you can't get without doing an in vivo model but the in vivo models are becoming much much better I mean the genetically engineered mouse model is now really do replicate a lot of the issues in human disease and I think as Jim suggested they're not perfect but increasingly we're understanding what their imperfections are and you can build that in so for example the lack of adequate numbers and mutations in these these genetically driven mouse models so now for example Tyler Jack's lab is adding this mutate or phenotype so that they will have some of that so I think increasingly the animal rules are going to be more useful and and they're actually going to become closer and closer to what we need to know to understand and predict what will happen in a patient I don't think they'll ever be a single animal model that's just we sure that's what people say what's the best well depends what the question is well Jim should tell us what animal model he use for discovering a anti-tumor effect of ctla-4 if we just want to get a dose of reality here which was a very is transplantable model so what I'm gonna open it up now to questions for the audience yes is all those microphones working behind I think if you go to that microphone there thank you all thank you all of you for the great contributions to the field of immunotherapy my question is directed to dr. Greenberg so we know that you know car works in the hematological malignancies very well but we also learned that you know certain from the certain TCR trials like you know beyond melanoma it has shown some efficacies but what exactly is that the TCR therapies and car therapies in different in terms of homing the tumor can you give us some insight into that well I there are obviously there's very substantive differences between a car and a TCR so a car which is this chimeric receptor that has an antibody on the outside and has a synthetic signaling module works very well in certain settings in particular as we talked about in leukemias and lymphomas and leukemias and lymphomas but it is much less sensitive than a t-cell receptor so first of all it can only target surface molecules second it needs a lot of surface molecules to be a signal so it whereas a TCR can see essentially all these internal proteins that get processed and put on the outside so the the the the range of antigenic targets with a TCR are much broader and they include much of the genes that are the proteins in intracellular proteins that are driving the malignancy but because they see fewer molecules their signal is actually kind of weaker so what we're trying to figure out is how can we synthetically design cells that will be more effective and so in solid tumors there are cars now that are showing some activity certainly in the animal models and none of being tested in people there are TC RS that are being tried in solid tumor models that have looked increasingly effective so i we're going to get there it's again there's a this is a field in evolution where we realize how recent it is that all this data can be shown to be effective but now that we see once now that we have a signal in diseases of efficacy building on that is really different than going back 15 years and saying we have no signal nothing so going from nothing to something was a was a huge roadblock going from something to something better is a whole different kind of a set of experiments and it's gonna feel it's gonna move very quickly and I think that's true of all the you know therapies because you know we now we now know it can't be done it's just a matter of yeah putting the right things together the big big burden is it's done now I mean that's that's what this celebration is all about here so my question is regarding uncle Eric viruses I think we've seen some very intriguing evidence that in combination with checkpoint inhibition they can be effective potentiate the activity profiles of checkpoint inhibitors and perhaps most intriguingly can attenuate the toxicities associated with search and certain checkpoint inhibition strategies but what I wanted to know was how you think they might be optimally deployed from an administration Route perspective the IV versus the intra term oral route and also whether you believe that Uncle edik viruses per se might potentially become the principal combination regimen modality or if you feel that there are already other modalities that have emerged in combination with checkpoint inhibition that have superseded what we have already seen so far with the alkalotic viruses or if it's just too early to tell thank you well question well we've we've got in my laboratory a little bit of experience with alkaloid viruses and they've learned a couple things one time is just killing the tumor cells are releasing antigens only one of the things you have to have happen the other thing is you have to really get to engage the innate immune system if you want to get particularly systemic community and make it really work I don't I don't think it's gonna take over as a major thing at all types of cancer but for some cancers you know where metastases are accessible readily accessible for sure you know to our intramural delivery of the viruses it's it's kind of a no-brainer I think in terms of systemic administration of them that'd be a lot better if there's some way to tag them and focus them on going to and finding the tumor and you know being really really specific which most of them now are not it is what it is a strategy we were talking about before how do you what do you do with a cold tumor it is a strategy for creating inflammation in a tumor that that can then potentially recruit in effective responses particularly if you're doing something like providing a checkpoint that actually will enhance the generation or activity of those responses so it clearly has a role there are other parallel technologies that are being pursued so there are nanotechnologies that for example you can inject intravenously and people are learning as Jim was alluding to how to tag these particles or even modify the viruses so that you could give them systemically and they would at least preferentially wind up at tumor sites and so I think oncolytic viruses are a very promising strategy for converting a tumor but it's not the only one and and so which of these uh which of these strategies will become dominant or whether there will be non overlapping settings in which one is good and and the others and and alternatively in a different setting where different technology is going to be good I think we don't know that yet but these are definitely promising strategies for changing the way a non-responsive tumor can become responsive well I think we're probably out of time so thank you very much Gerald and we're gonna take a 5-minute break now and then we'll be back for our our industry panel [Applause] thank you everyone that was such a fascinating discussion I can imagine folks didn't want to come back in from coffee because there's so much to talk about so we'll continue the conversation now and I think this is such a wonderful order of events because of course things begin in the laboratory and then pharma biotech often take it up although I'm sure George would say you originated many things in your labs as well but you take that science and that research and you turn it into products and so this is gonna be a wonderful discussion I'm sure you know these folks here on stage with me but we've got dr. Oney feta jela today did I get that right that's correct all right from bristol-myers the US head of medical for bristol-myers and Georgie and kabbalists from Regeneron chief scientific officer president and founder we've already been having a fascinating discussion and we're gonna open it up to questions in about 25 minutes so please get ready and and come to the microphones and join in and ask questions so let's begin by kind of setting the stage for where industry is an immuno oncology and and only let's start with you you know where where do you think we are in terms of you know the the timeline of amino oncology and really reaching its promise so certainly you know we are still at the beginning of the oncology that I don't think a lot of things that we will need to continue to do we've heard of things for Jim and other the panel before we have made a lot of strides getting patients a lot of you know hope for survival I think we have a lot of more work to do a lot more work for patients that are developing io resistance a lot of work with covering other platforms and new platforms where we are able to get there and drive to this long-term survival promise that we're thinking about George what do you think yeah I think it is a so first of all I think it's one ecosystem I mean we work so tightly with so many people in academia and we're all part of the same effort so I don't think there's separate efforts in academia and in history we're all in this together and I think it's appropriate and it's a great time to celebrate the major advances and the the breaking open of the immune approaches towards cancer but Wow we can pause and celebrate a bit I think it's it's also critical for us to you know reflect a little bit on how hard the challenge really is and and how hard the biology and the cancer really is here and I think we all have to recognize I think Bob touch on this a little bit is in most cancers so far immunotherapy hasn't really made a dent you know despite the thousands of trials that Jill referred to most of them have not really shown much advance over some of the early data with the checkpoint inhibitors and the combo that approaches to date have been disappointing thus far and you look at some of the biggest cancers prostate pancreatic colorectal there's really little advance in those areas and so we need to all together in our ecosystem up our game and and and figure out how to take this promise and really deliver and hopefully deliver a lot sooner because I would actually say I I am very when the first day ii started coming out on checkpoints and so forth i thought that by now we would be you know by 2020 would be a lot further advanced and we are now and i think we we all have to up our game and figure out how to really take these early advances and take them to the next level so i do have a different opinion here though so i think i think it's really important i think we've made a lot of advances i mean the work that jim has done the work that we have done with pd-1 the combination therapies we have seen advances in the therapeutics of lung cancer we have team that Wenzel 300 melanoma reno while we have not cracked the codes on some of the tumors like pancreas and prostate there is definitely with the combination of CTL a and pd1 we have seen overall survival in renal cancer we have seen Russell Varon melanoma we're still exploring a different tumors so I think there is definitely advances note we need more work I agree we definitely need more more work and what there are certainly things that we will need to continue to do but we can't do it alone it's gonna have to be continued to collaborate as George was saying but I beg to differ a little bit on where the advances that we are how do you as leaders of organizations make decisions about where to allocate your focus and your money we saw at the beginning that there are more than two thousand combination trials going on obviously you want to follow the science but you also have to think about the commercial landscape I assume how do you decide where is the right place for you to focus George well we we go where the science takes us we generally don't use commercial insights to make the decisions for us it's all based on the sides and I mean the thing that I'd like to touch on is I do think that there's a lot of new exciting approaches that weren't brought up in the first session certainly ones that we're approaching because we thought that they were great opportunities years ago because you know we all know these take years to take things forward so we're obviously very impressed with the cell therapy approaches I think they're very exciting but complimenting them and in some cases may be opportunities to improve on them are these by specific approaches and so we've invested heavily in that because we thought that the science warranted that and they often also afford great opportunities for combinations with foundational particularly pd-1 type therapies and approaches and so you may have seen you know we recently at recent European meetings updated our latest data with our by specific and they're now producing data that is looking very competitive if not you know more impressive than Carty therapy in fact we've tried it in Carty failures and now seeing very high response rates so we really think that new science new approaches that can really take things to the next levels layered on top and in combinations we've actually shown impressive combination opportunities between these by specifics and the PD one class in particular and we think these can unlock the immune system to now start giving results not only against the liquid tumors and the the human logic malignancies but also against all tumors and also prostate and and and and so forth so we're very excited about the future about new approaches and new technologies honey how would you describe bristol-myers is take on on cell therapies and by specifics you've got into cell therapies in a much bigger away with your acquisition of cell gene how would you just describe the way the company is sort of involved in that thinking you know I think I think with the acquisition of cell gene and were two separate companies till it actually happens I mean I think that gives us a frontier of to go to cell therapy and good rooting both them it was mentioned the BCM a and and the court either to the cd19 I think the now that well that we have we would have hopefully the platform accessible to us we'll be able to look go more broader than cell therapies to mm-hmm what about by specifics the by specific technology this technology that we've been looking at I mean it's another technology that is EMS has worked with I see and is Regeneron exclusively in by specifics would you go into South air B's Carty things like that you know we constantly are comparing and testing so in our own labs we are heavily invested in car tease and buy specifics and ways of actually we actually believe you can combine those as well and and get actually more specificity without sacrifice and more efficacy with that sacrificing toxicity so we think that you can't be in this game unless you have you know all the weapons at your disposal plus we have major collaborations with Bluebird and with data set in in the car to space so no we're we're believers that it's going to take all sorts of different weapons to really really try to do a good job at addressing all of these cancer challenges that we're all facing and you have to pick and choose the right weapon not oh I'm into by specific so by specifics are gonna you know it's the right hammer for every nail now now you know cell therapies it's the greatest and the latest now you know checkpoints by themselves or alone no I think it's going to be the right collection of approaches for the right setting and having the ability to have all these weapons your disposal and choose the right one for the right setting can allow us to start getting I think much more impressive responses in the right in the right settings so I think it goes to the precision medicine that we were talking about earlier who's that how you're able to find the right medication from the right patient and with all the tools that are available to us but it is not from my perspective it's not one companies can do this it's really takes the whole community together we'll be able to do this partnership with academic centers partnership with our hosts like our host doc CRI and also a partnership within the industry if we're not able to do this collaboration together and get these pieces together we're not gonna be able to advance the science I thought the discussion about biomarkers that you had was really interesting and the idea that you know there isn't a biomarker that excludes patients from responding and and perhaps you brought up the idea that you know patients who are failed by therapies aren't tested for the biomarkers to figure out what what might have gone wrong I mean how much are you guys doing that and trying is that important for you know drug companies to figure out why patients don't respond to it or if there's a marker that would exclude them from responding I think it's critical I think it's critical to understand the patient are not responding we have a lot of work ongoing work right now in and our big platform of area of interest is IO resistance and patients who are not responding to our therapy again we're collaborating with Jim's labs and other labs then how try to understand that but most importantly we just opened our site in Cambridge that is focused exclusively on on IO resistance which we have about 300 researchers across different disciplines looking there the most critical thing here is that it is is not just to understand the exclusion they said their resistance but I'll get to the patients and do exactly what Jim was telling earlier understand the journey of the patient the biopsy journey of the patient and what the tissue how things are evolving what do I mean by that so what happens before the patient starts therapy after they fail that and try to understand what's changed and how we're able to address it and and as a an example to that we have just announced a collaboration with one of our the Boston Medical Center where we are looking prospective that exactly what was being said earlier is getting the patient before diagnosis getting biopsies throughout this journey and trying to do to have it national medicine trying to do the the translation work that we need to understand why patient are not responding but what's most exclusive about this as well as that you need to get to patients are from different backgrounds because we are patients or our clinical trials may not necessarily reflect the patient's that are that we treat they today whether from ethnic standpoint or from gender standpoint so I think that allows us when you go to inner-city and some cities institutions to get those patients and try to understand the biology and why they are developing that resistance well I mean there's nothing new here this is what we've all been trying to do you know forever in every field of biology where you have any sort of treatment you try to understand why patients are responding and why they're not in you can understand the biology and the mechanism behind that you can then of course try to turn non-responders into responders and increase your rate of benefit so we've all been trying to do this in every field and certainly in cancer since we've all been you know studying cancer and of course it's challenging and every time you have a breakthrough they'll take the level of you know benefit to patients up another level so once again it's a fundamental biology you know nothing really fundamentally new other than that we all have new tools and new capabilities and new treatments that we will now you know be querying this way but this is what science has been around doing forever how much are you looking at the microbiome in terms of its role you know obviously the microbiome is important and going to be proven important for a lot of different settings and indications but I think it's it's sort of like everything else right now it's you know one of these hot areas and it's oversold and too much value is is being given to it I think right now we're gonna certainly find areas and applications where understanding and dealing and manipulating the microbiome was going to have a benefit but it's like any one of these fields in its infancy that it's going to cure everything like stem cells we're going to cure everything a few years ago and we're going to find out that right now I'm sure that almost everything that's being so you know talked about and so forth is heavily oversold in the microbiome and I think we take a different approach we are actually building a microbiome program and all our clinical trials try to understand what's actually happening there I mean it is it is important for us to understand it and I think you know we we know that there is a role that we just have to systematically and scientifically approach it George I mean that doesn't leave me to wonder and how can you be so sure that it's oversold or overhyped well because anybody who pays attention to signs this level of science this much enthusiasm based on almost no convincing data the way science works is most things don't deliver on promise based on no data so I'm not saying we know we know like c-diff is a disease of the microbiomes i'm sure there will be diseases of the microbiome but I can tell you in our own field as you may know we have an important drug for allergic diseases like asthma and atopic dermatitis there was a big story that oh my god the micro or the skin microbiome of people who have severe atopic dermatitis disease where more than half your your skin surface is covered with these horrific poison ivy like lesions that their microbiome is very different yeah big surprise I would think you're you're literally leaking fluid into your skin of course your microbiome was going to be different and there was all these people who were basing theories that it was the microbiome that was driving the disease and if we could fix the microbiome then you know you'd benefit the disease well you give them doop ileum and you actually fix their skin and what do you think happens to the microbiome it totally normalizes so cause and effect is really important here so I am like I said I mean science tells you when you have little data and you have great enthusiasm most of the time that enthusiasm is is unwarranted but that's exactly why you need to study it right so that's you're able to understand I'm not saying don't study it I'm just saying it's not going to be the cure-all that's all I say okay I guess I'll leave the microbiome or on him you know there are these guys I mean I think we were talking about the microbiome in terms of its impact on checkpoint response right so what do you think of the data that you've seen maybe we're just gonna have the same honey gut yeah I mean keep going forever there's very little convincing data but I think we're still determined that we need to understand it we need to study it we don't know that that's this that's really what we need to understand yeah okay so another area that some folks might call overhyped is is AI and machine learning what do you think about that George well the most well we I we are huge believers in machine learning we don't like to call it AI because there's nothing really intelligence about the approach it's just pattern recognition and it depends on big data well-structured big data and in our field the hardest thing to do I mean is you know it's a lot easier when you're Google and you have you know essentially buying and googling patterns of millions and billions of people you're creating huge amounts of well structured data that they can then take advantage of to figure out how to how to how to capture our attention and and and our buying you know tendencies in our field we need to create the big data and that's the hardest part the machine learning is not really going to solve things if you don't have huge amounts and in many cases you really need much much larger data set than we have available to us as you know our Regeneron genetics under many efforts that we're doing we're investing hundreds of millions dollars to create the data which you then can take advantage so machine learning is not going to solve the lack of data problem and in fact you're gonna when we know this is better than anybody if you do machine learning on poor data sets you're going to just get fooled and over enthusiastic about the wrong theory so machine learning is not the limiting factor here it's a great tool you need to create the really valuable big data sets he has bristol-myers using machine learning and big data so we're losing stream we're again it's it's an early technology and what the way we're using it is more in the pathology space where we look trying to do machine learning on pathology slides where we're able to follow the patients and we're able to kind of identify patterns that's the big area that we're using it in we do need large data sets to be able to understand this what you teach the machine to do and how to analyze that's certainly a limitation but that's how we learn and we continue to forge into that how far are we from from getting to the place where you have good data sets enough data to actually do this kind of work well I I think in certain areas you will have you know data sets sooner rather than later but you know it all depends on your goals and and what you're excited about and I they're not going to give you the theories they're not going to tell you oh you know you know checkpoints are the right pathway that's really still going to come from you know you know novel genius human insights that's not going to come from machine learning machine learning you know recognize patterns and data sets that are then going to provide you with hypotheses and with patterns that you can then hope to take advantage of but it's once again it's not going to be the be it and the end-all it's going to be a useful tool going back to the idea of trying to extend immunotherapies reach to cancerous that that haven't been served by it yet one story out of ASCO was around tumor infiltrating lymphocytes with company called iya Vance working on taking cells that just exists in the body you guys can explain this so much better than I could but really not necessarily doing anything special to them but just finding the cells that are already working and multiplying them and giving them back what is your thought on that approach I think it's a it's a it's a new platform that is opening to us we need to understand how it works better anything that we are able to understand to collaborate understand the biology that's the main important thing and partnering how we can bring this to the patients we still need to understand yeah I mean it's what we heard in the previous panel it's going to be the collection of positive and negative signals that are going to drive different components of the immune system to infiltrate an attack a cancer cell and there's you know obviously there's many pathways that we're all trying to manipulate there's all sorts of clever new approaches turning a negative signal such as PDL one into a positive signal I mean those are all sorts of things that I think that we're all going to be trying to do to increase you know the benefit now that now that we've made you know thanks to Jim this big insight that we can harness the immune system we got to do a collectively a better job and it's going to involve all these different new ideas that people are talking about and I think they'll be you know incremental advances and hopefully will crack prostate that will crack this or you know maybe there'll be a big breakthrough that allow us to more broadly do this but this is why we all need to be you know investing in the research at all levels and in the science and in the clinical work to try to advance the field what's in your lab right now that you're most excited about in this area well as I touched on I think that you know we do believe that pd-1 is a foundational approach and we're trying to layer on top of it I see we have our own PD one that we think has produced exciting results on its own but now we're layering on it with these by specifics which in a sense are sort of doing and allowing us to do what cell therapies do but in an individualized manner where you can literally dial them up and dial them down so we have two classes of by specifics the first class which literally brings and activates the t-cell to the tumor which they work on their own like I said on their own they're having very impressive efficacy but we've now shown in animal studies an emerging human data that combined with PD one they work better but now we have a whole novel class of by specifics that I think is the most exciting thing to us which are these things that actually bring co-stimulation so we've all heard of co-stimulation the second signal that can hyper activate the t-cell so we have by specifics that activate a co stimulatory signal only when it attached to a tumor antigen marker and you can take advantage of combinatorial specificity there and I know that the the cell therapies are trying to do a lot of similar things but there would be a huge advantage in being able to dial these things up and back and give them and test them individually individual combinations and then the convenience of being able to give them in a controlled manner to patients so giving coasts in by specifics with the more traditional city 3 by specifics layering them on checkpoint therapies I think these are the sort of approaches that we're excited about and thinking we think can take approaches against individual cancers to the next does he think about layering and then you do start to worry about toxicities and you are talking about very targeted approaches does that take care of some of these concerns and what have you're seeing in terms of well that's why we think this this is why we are heavily you know big believers and invested in the cell therapy approaches we are you know very excited about these by specific approaches because they can allow us to individually test pathways and dial them up to different degrees and often in the same patient you can slowly give one in the other as a low he's here now has shown with these by specifics that you can really control the toxicity by gently dialing them up or down as need be and if you can do that with your different combinations I think you could attain maximum specificity and target activity without or with controlling the toxicity to a great degree I want to give you guys a two naff minute warning if you have questions why don't you head toward the microphones and I'll ask the same question of Arnie what's going on in your labs that's most exciting to you in this space now so we're really excited about what we try to do with with CTL a the next generation of CTL a the pro drug for CTL a which exactly is trying to avoid to deliver the efficacy but avoiding the adverse events or minimizing the adverse events I think it's an exciting technology that we're seeing in faith now it is in our laboratory right now we're also very excited about our locally the antigen to do antigen presentation the NIS 3 the the sting mechanisms these are things that were very these are molecules that are helping us really create antigen and and to begin to attract G cells inside of the tumor so these are technologies that were very happy to be working with they're now in phase one phase and we're waiting to see what this clinical effect oi and we're also excited on some of the technologies that we are you know we probably will we will be working on an in Cambridge where we're trying to understand the exact trying to understand map the take T cell that he cell morphologies mostly for anatomy around the tumor so that's the technology that we're working on to try as as we mentioned earlier is really try to understand the 360 view there okay we've got more questions for you but we've got questions back here so why don't you go ahead my question is with respect to antibody drug conjugates and where you see the future of that field heading I mean historically it's kind of waxed and waned people have been by degrees impressed and then disappointed with the potential of AD ceases hole and in particular how do you see that field developing with respect to the likelihood that the success or failure of any particular ADC therapy is based on the target versus the payload thank you well once again we're invested in ABCs we believe that you know the right approach in the right setting that said I do think that the power of for example either a cell therapy or a buy specific against the same target might have more promise I think that the ABCs would have role if your target is not as specific as you would want and you don't want to maximize anti-tumor efficacy because of the toxicity but I like I said we are trying them and we are advancing them and putting some in the clinic in the right settings but you know I do think that if you're trying to maximize you know tumor kill you know I think some of the other approaches with cell therapies and with by specifics have more power in them that's my personally I think a DC's will continue to have a role in cancer therapeutics that just depends really on the biology of the tumor that's dealing with and the combination of things that you need to put together to attack this tumor or to so it is really depends on what the biology that we're dealing with and that's the most critical thing understanding what's happening at the tumor time Brett question for George you touched on this a little bit but the cd3 by specifics it seems that all companies are having issues with talks right now the cytokine release syndrome and I think it's actually very similar to what the Karthik treatments went through in the very early days with that and they eventually got a hold on it so I'm wondering have you know how you feel like where you are with that and whether you're concerned that that would limit the clinical or commercial utility of that type of approach in the future or if you think you'll get a handle on it yeah well you may have heard that roast just announced with their they basically in terms of cd3 by specifics I would say that we and Roche are sort of been neck and neck and lead in this space and they've created a number of different platforms and they are one platform that was looking from the efficacy perspective somewhat competitive with ours is what they call their two-to-one platform and they just announced today that they had when they were trying to dos escalate they had some serious toxicity issues and now they're only going to be moving forward with the lower less effective dose levels I think that our advantage is our platform is a unlike almost every other by specific platform it's a totally natural platform a lot of the component in the the by civic is really founded on a natural mouse platform that we created that helps us generate these by specifics and because it's much more natural we've actually seen that we can give them to control the way I mentioned that Izzy LOI who's here today who's led this program figured out a way to sort of gently dial them up and when you do that you gently sort of rev up the immune system presumably killing off tumor cells more slowly and then you can finally ratchet up to really high doses while avoiding much of the Texas so right now we look like you know and I hope for patient's sake that we have managed to get two very effective levels like I said where we're seeing car TF like efficacies or even efficacy in car t failures without the sort of toxicities that have that have hindered some of the other programs so we're really pretty excited about that I should also say the cd28 by specifics that I mentioned on their own we see so far almost no toxicity it's very related and for those who are not aficionados who don't follow all the specific molecules our cd25 essentially are activating the same pathway that ctla4 tries to unleash but ctla-4 blockade will only work in the setting where that where CTL floor is actually blocking that pathway and it's working in a relatively less specific manner with using a targeted by specific we actually target activation of this cd28 pathway which is normally being blocked here with the CTF 4 but now we can get activation even where there's no endogenous CTL a role plus you avoid the generalized toxicity of blocking the ctla4 in other places so these are all a lot of the same pathways that we're talking about it's that the more targeting the more precisely that you can do it and the more I think you can dial it up and down individually then the greater the chance that you have to deliver more benefit with less toxicity we're talking a lot here are there more questions oh sorry even see over there hi I'm wondering if you both could talk from a high level about autoimmune research and the extent to which advances there is informing immuno Oncology and vice versa and how you think our MD organizations are gonna think about those two fields going forward you know I think all the immune research and is really a critical element to help us understand how the immune system operates but also it's the flip coin of money over activate the immune system so it will it is actually a now that we have the patients that may develop autoimmune there's adverse events it's actually arrived understanding that are in the organization's start thinking how we all understand those patients how to study them and also how to solve for them and certainly it is it is the check balance between the two elements so definitely as we start understanding immune mediated adverse events we learn more about autoimmunity yeah I think it's incredibly it's a great and very astute question and essentially almost every pathway that we're looking at for cancer to try to increase targeted immune responses against the cancer we're querying and evaluating and creating reagents and actually potential therapeutics to almost do the flip side as Ani said to try to treat autoimmune disease so so we do think that they're the opposite sides of the same coin and if you can promote them in the targeted fashion you can actually hopefully control them in a targeted fashion and treat autoimmune disease for sure so I think it's a great question which targets are our most promising that you see there could we see a sort of checkpoint yeah I mean I think you know Jim did some experiments years ago where he actually put some essentially checkpoints into for example you know the cells that you lose in diabetes and show that you protect against diabetes and autoimmune loss of those cells and and so yeah we are following up exactly on those sorts of a you know fundamental experiments that were done several years ago now to do exactly that now with therapeutics we're doing the same thing what are you looking at this from a therapeutic standpoint at the risk of opening up a can of worms when we've got only a couple minutes left we haven't talked about pricing of these drugs of course they are very expensive drugs the branded drugs an immuno Oncology and as they're getting combined on top of one another how much are you thinking about that you guys are leading science so you think about it differently but but how does that come into how you think about development in this area I think your prize to drugs based on the value of your brain I don't think that the issue was pricing it's just drug pricing I think it's a healthcare system pricing issue and that's what we need to look at it collectively rather than just drug pricing so that's that's that's gonna be the critical thing that's conversation that we need to have well I I do personally think that unfortunately compared to actually drugs outside of the cancer base I think that most of these cancer drugs are a little too highly priced and I think certainly because we're talking about combinations that we're going to have to be giving that we're going to have to figure out to come up with a much more responsible way to control pricing there because you can't be layering $150,000 drug on top the drug the cost of that much as well and and and I I think that you know we're gonna have to deal with that and if we don't if we don't figure out how to deal with it somebody will figure out how to deal with it you know for us so I think as an industry I think unfortunately a lot of the industry is being propped up by cancer drug prices and orphan drug prices to the you know you know to be negative impact in other spaces and I think there has to be a little bit more balance in the pricing arena is the answer to that when you're thinking about it in immuno oncology combinations having to wholly-owned all of the drugs in the regimen so that you can create a new price for the combination I think that that that might be one of the approaches to try to control pricing absolutely but what if you don't what if the science leads you to say okay well this other company has the best one in this class I need to combine with that I mean how do you work I mean you can't really work together I'm pricing gives our laws against that but how do you figure that out look I think that we're gonna have to figure that out the challenges no because I don't think I first of all I think it's wrong and secondly like I said I mean I think society won't tolerate you know layering on top two or three drugs of these prices and even if it is in cancer and even if you're providing you know a big benefit I I think that we have to figure out a better way all right well we'll leave it there thanks guys thanks everybody [Applause] so it's my pleasure to close out our discussions this morning really to announce and tell you about our Lord jailed star program this is a new program that the Cancer Research Institute initiated really at the behest and at the advice of Jim and the other associate directors of our of our organization saying that there was an unmet need for mid-career scientists there was a lot of support for young scientist but that mid-career was a time that really could you know really by supporting this you could really change the field so we created this program to give significant and sustained funding to what we are calling our stars because these are the people that I think are going to bring our field forward this is a grant that is not directed to a specific project but rather it's to the person so these are people that have had great track records already and that we hope by giving them this grant that they take risks follow paths which they you know may not have thought of initially and that they are going to be the people to follow and then track for the rest of the year so here they are I'm happy to have them woops sorry one there's five of them we gave five awards this year three of them are here and I'd asked them to come up to the stage and shake hands with Jim and get a great photo-op come on Jimmy can come up here come up here so here we have Yvonne Chen from the University of California we have a mandolin from Oregon Health Sciences and Greg Sonnenberg from Wilde Cornell after you all come on up congratulations on getting this great awards great yeah y'all come up here and get up on the stage next year get one good picture and then unfortunately two of our stars couldn't make it today but they are Alex Marcin for the use of california san francisco and andrea tenderer from ms KCC so we are thrilled and we expect great things from you and please these are the people you should follow these are our future the future of cancer immunotherapy so thank you very much you

Channel: Cancer Research Institute

Views: 12,010

Rating: 4.727891 out of 5

Keywords: immuno-oncology, jim allison, james p. allison, md anderson cancer center, robert vonderhei, bob vonderheide, penn medicine, philip greenberg, phil greenberg, fred hutchinson cancer research center, fred hutchinson, immunotherapy, checkpoint inhibitor, microbiome, regeneron, fireside chat, bristol-myers squibb, Awny Farajallah, George D. Yancopoulos, Meg Tirrell, CNBC, cancer research institute, cancer research, a future look, IO, cancer immunotherapy, immune system, cancer

Id: 6mwK3Ylh_VU

Length: 93min 2sec (5582 seconds)

Published: Tue Jun 25 2019