#267 ‒ The latest in cancer therapeutics, diagnostics, and early detection | Keith Flaherty, M.D.

Hey everyone welcome to the drive podcast i'm your host peter attia this podcast my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen it is extremely important important to me to provide all of this content without relying on paid ads to do this our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free if you want to take your knowledge of this space to the next level it's our goal to ensure members get back much more than the price of a subscription if you want to learn more about the benefits of our premium membership head over to peterattiamd dot com subscribe my returning guest this week is doctor keith flaherty keith was a previous guest on episode number sixty two of the drive way back in july of twenty nineteen keith is currently the director of clinical research at the massachusetts general hospital cancer center and a professor of medicine at harvard medical school and he serves as the editor in chief of clinical cancer research a very prestigious journal his research focuses on understanding novel molecularly targeted therapies in cancer within this field his focus has been on the development of response and predictive biomarkers to define the mechanism of action and resistance of novel therapies as well as to identify the optimal target populations in this episode we start by looking at some of the statistics around the prevalence of cancer as we age this really highlights the importance of this topic and although we don't spend a lot of time on it because i think intuitively people understand that i i do think it's important for people to understand progress we then of course shift to what has been done and what has not been done over the past several decades and there have been some very notable improvements in cancer therapy over the last ten years which we highlight from there we shift our focus to looking at what is on the horizon and what the future of cancer therapeutic holds both in the short term and in the long term and i think that even within a five year period there are some incredibly exciting things that look to build on the successes of the past decade we also talk about liquid biopsies which of course play a very important role in early diagnosis of cancer and we talk about the state of the art today but again what we think it's going to be in the future and this is something that you've probably heard me talk about in the past liquid biopsies have the potential to diagnose cancer from a simple vial of blood where they not only can determine if a cancer is present in an early stage but also identify the possible tissue of origin now a lot has changed since keith and i initially spoke over four years ago which is why i thought it made sense to have him back and talk about these things again and i will say this conversation was illuminating to me and it certainly won't disappoint those of you who are interested in cancer so without further delay please enjoy my conversation with doctor keith flaherty hey keith great to be back with you again hard to believe it was almost exactly four years ago that we sat down in boston to do what will be part one of this discussion but you know we've got a lot more listeners now and it's not like some of that content isn't still relevant today so we'll probably talk a little bit about some of the things we spoke about then but there are a number of things that i am excited to discuss with you that we haven't talked about and i suspect that will make up the lion's share of our discussion so thanks again for.

Making time yeah thanks peter it's a great pleasure to talk with you again and yeah you're right four years a lot has happened in therapeutic development maybe you could have said four years ago that some of the things that have played out would have played out but on the diagnostic side i think that's probably where four years ago i didn't quite have the crystal ball vision as to how things would develop there and of course those two areas are tightly related in oncology so excited to dig.

Back in let's just start maybe give folks a short background a little bit about what you're doing and why it is that you're at least in my view in a great position to talk about cancer in a way that is more than just an inch wide and a mile deep which is the general nature of the field but several inches wide maybe and several you know and a mile deep like what is it.

About your background right i'll try to hit some highlights here that make that point so i'm a medical oncologist i've been in the field now for twenty three years which is a relevant number because of the fact that the first translation of molecular insights specifically genetic insights into cancer biology really became therapy starting that year that's when amat niberglievec was first inpatients and was kind of a revolutionary moment my career started right then and there myself interested as a medical oncologist in trying to translate science to medicine in very much that way like taking insights in terms of the genetic makeup like the mutations and the sort of mutational architecture if you will of cancers and trying to translate that understanding into therapy so i've been doing that for twenty three years like anybody in the academic medical world and oncology i had focused on specific cancer types of melanoma and kidney cancer and both of those i chose because of the molecular insights that existed at the time that felt like they were at least beginning to be ripe for translation so i did that work for about a decade at university of pennsylvania moved to mass general part of the harvard university umbrella harvard medical school to build a clinical program focused on therapeutic development much more broadly across cancer and then i think as we'll talk about this interplay between therapeutics and molecular understanding and ultimately diagnostics basically built a translational research group surrounding therapeutic development what i refer to as bedside to bench translational research to sort mechanisms of action mechanisms of resistance in other words when drugs work why and if they don't work you know why not and use those insights to try to kind of accelerate or drive the whole process forward and then i'll just throw in also that over the past ten years i've co founded now a handful a little bit more than a handful of biotech companies with loxo oncology being the first ten years ago when i was acquired four years ago and scorpion therapeutics being the most recent and i'm actually sitting in the offices of scorpion therapeutics at the moment and so through those channels i guess i would say it's my job to keep a steady eye on new therapeutic concepts that could be ready for primetime to move forward and then again trying to translate micro understanding into tools that we can actually use for real patients aka diagnostics.

And keith i think it's always worth repeating to folks what it is about cancer that's as far as the big four chronic diseases i call them the four horsemen in my book there's something about cancer that's particularly damning which is when you look at the other two chronic diseases that are huge killers which are cardiovascular disease and neurodegenerative disease they increase in their severity exponentially as you age and they don't really become a dominant source of mortality until people are in the seventh and eighth decade of life and that's not true for cancer in fact i have a little table in front of me that i had one of our analysts pull together that i think is just we'll put it in the show notes it's very powerful right so it's sort of looking at people in ten year increments just from twenty five to thirty four thirty five to forty four et cetera all the way up to you know north of eighty five and it lists the percentage of people in each age category that die in response to cancer and here's what's interesting is that number peaks in the middle right so at twenty five to thirty four it's six percent thirty five to forty four it's thirteen percent think about that for a minute that is a staggering number for people so young by the time you get up to forty five to fifty four it's twenty three percent fifty five to sixty four thirty percent sixty five to seventy four thirty one percent and then paradoxically it begins to come down after that because those other diseases are taking off another way to look at this is where does cancer rank in cause of death for all causes by decade and if you go in those same buckets starting at twenty five to thirty four it goes from third third second first first second third in other words it's always first to third there is no other disease that always ranks in the top three cause of death for every age that's it full stop period it's cancer and so it's the second leading cause of death overall we can talk a lot about those stats but there's nobody who's listening to this podcast whose life has not been affected by cancer that wouldn't be possible i don't think you could come up with an example of someone who doesn't know someone who's at least had canc and it very likely died as a result of it.

Now that's a good reminder you know one interesting thing maybe just to break that data down a little bit you know people think of pediatric cancers of course those are like if your life has ever been touched by a kid with cancer there's like almost nothing more jarring you know almost seemingly unjust if you will about a child being diagnosed with cancer for children cancer's quite rare it really occupies an enormous amount of mind share but then as you go into the decades that you were summarizing what's interesting is to reflect on the cancer types you know that kind of lead the way so brain tumors leukemia melanoma the most deadly form of skin cancer you know one of the cancer types i mentioned that i've been focused on my career long you know that really jumps up in those twenties thirties forties those cancer types kind of lead the way in kind of the younger population and there's some interesting implications there in terms of like well what causes those cancers and some people you know so vulnerable to them and then you know carcinogen induced cancers well melanoma of course is there's a carcinogen called ultraviolet light that's a carcinogen for skin cancer including melanoma but like smoking related cancers for example those really start to jump up in later decades and then you've got everyone is aware of this but obviously lung cancer leads the way there but there's a smoking footprint for a bunch of other cancer types that people don't think about so much head and neck cancer is one that i think is you know relatively not top of mind for people but you know even when you get to bladder cancer which you'd think oh how does smoking cause bladder cancer but it's not the sole cause but it's certainly a big contributor you know these sort of smoking related cancers they take exposure obviously and a bit of time to accumulate their population impact ultimately and just one other thing that i would kind of throw in there because i'm sure we're going to talk about the really population prevalent cancers breast cancer prostate cancer lung cancer colorectal cancer the big four so breast cancer and prostate cancer are not related to well obviously ultraviolet light or smoking so much i mean a little bit of smoking influence on breast cancer risk but there it's this really interesting interplay between these hormone receptors hijacked or co opted in a way and you think about the way in which those cancers form i think it best fits your age cardiovascular disease and neurodegenerative disease i would argue there's something at play there that's similar to these hormone driven cancers which are very age related so breast cancer and prostate cancer really pick up in those later decades of age so it's just kind of interesting to reflect on kind of the how and why different cancers kind of feature in those different decades of age and that has tons of ramifications in terms of how we think about screening which i'm sure we'll.

Get into yeah for sure so let's add a little more color to that keith so you mentioned the big four lung being number one i think a breast and prostate is kind of number two and colorectal number four and then if you add a fifth in pancreatic you now account for a little over fifty percent of all cancer deaths so you know we'll talk about incidents but we're going to talk about mortality and at the end of the day just five cancers account for half a little over half of all cancer death in the united states that's one point i'd make second point i'd make that's very interesting when it comes to breast and prostate is on the one hand we have this clear understanding of the role of hormones and yet as you point out the implicated hormones are actually at their lowest levels when these cancers typically come on board so we talk about the relationship between testosterone and dihydrotestosterone dht and prostate cancer and yet when men have their highest levels of these hormones in their twenties in their thirties and even in their forties a cancer is never to be found eye cancer shows up only when those hormones are long gone you know not gone completely but of course greatly diminished and the same is true with breast cancer right we see the incidence of breast cancer going up but it's not necessarily hitting at the peak level of estrogen in women there's more complexity to it but again it speaks to just how much is going on beyond the surface and the first order thinking yeah no that's a.

Great point and actually it's kind of very tempting to insert here you know sort of deep cancer biology principle if you look at other cancers than breast and prostate the cancer types where we've really gone the deepest in our understanding of what causes them to become cancerous in the first place and even in terms of translating that in terms of therapies it's really been around the growth factor receptor and downstream of growth factor receptors like so on the surface of cancer cells and then internally that's where the action has been and here's the point which you just made about the hormone receptors is that basically cancer cells quote unquote figure out how to become independent of the actual growth factors themselves so they basically turn through genetic mutation or alteration they turn on these surface receptors or the immediate downstream signaling molecules from those surface receptors it's mutations there that's the absolute like nidus if you will the hotspot of where most cancers not all but where most cancers actually get their kind of oncogenic drive you know the mutations that drive cancer again really analogous to the comments you or the reality and the comments you made about prostate cancer and breast cancer in terms of basically that the circulating hormone levels at the time those cancers manifest are low what's happened is cancer cells have wired themselves in a way to be sort of autonomous or independent of those ligands but still using the receptors and their downstream consequences to drive those.

Cancers and i wonder if there's a parallel between the following observation which is a prostate cancer that develops in the presence of low testosterone all things equal is a worse prostate cancer so there's that paper in the new england journal of medicine god it's probably been fifteen years now that demonstrated very clearly that the lower the testosterone at the time of diagnosis of prostate cancer the worse the outcome very counterintuitive right everybody thinks testosterone is causing prostate cancer when in fact what we're seeing is so i wouldn't interpret that to mean testosterone potentially has zero role or that high testosterone is protective although some have argued that what i would argue is your point which is that the cancers that grow without the hormone are worse and therefore the parallel if you will is the erpr negative breast cancers are worse than the erpr positive breast cancers those cancers those typically hormone sensitive or driven cancers that proliferate whether it be the initiation or proliferation without their respective hormones tend to be the harder ones to combat.

That'S right so in those instances those cancers have actually figured out how to essentially replace the function by virtue of accumul i use language like they figured out i think you might remember from.

Our conversation yes we like to anthropomorphize.

Cancer exactly i was just going to say i love anthropomorphizing cancer actually from a therapeutic development perspective it's like the easiest mindset to sort of adopt in terms of thinking about how cancers solve the problems that they need to solve to become cancers like it's kind of scary language to use i realize but when you're trying to then reverse that or intercept that it becomes a little bit useful so anyway the point is that there's a constellation of mutations that can turn on essentially the downstream pathways for example estrogen receptor so what's driving then a so called triple negative breast cancer so lacking hormone receptors and lacking her two which is a well established surface target a growth factor receptor on normal cells and on cancer cells including breast cancer cells for cancer breast cancers that have figured out how to become breast cancer what you see in their genetic makeup is that they basically still are dependent on the same sort of cellular processes they still have to kind of regulate the same downstream programs they just do it through a variety of means and ones that become very challenging to directly target to like to intercept those and so the point you're making about breast cancer i'll just maybe complete a little bit this way which is you emphasize that their prognosis is better right so in other words before ever talking about therapy those breast and prostate cancers that form and stick with breast cancer because that spreads across younger ages you know a bit more than prostate cancer does their prognosis is better so before even coming to the issue of treatment but their treatability is also far greater because we've got drugs we have more targets exactly and intercepting those hormone receptors specifically which are by the way inside of cells just a little nuance to separate from the comments i made about sort of those surface growth factor receptors those drugs we've had them for a long time but also like serious advances have been made applying new chemistry strategies to developing even better and better versions of those so what we're witnessing let me just make this point in relation to pancreatic cancer which i'm glad you called out is that i might have used this term four years ago we have this scenario in cancer where there's kind of a distribution of haves and have nots and what i mean by that is we have patients whose prognosis to start with is better and whose therapy advances are really accelerating and like making certain cancers and hormone receptor positive breast cancer is quite a good example of this where additional drugs now have been successfully developed and its combination since we spoke four years ago even now fda approved and on the market and so the outcomes of those patients just continue to be distanced from cancers like pancreatic cancer where first off the lethality of pancreatic cancer per case diagnosed the case fatality rate so called is far higher than these other cancers right so it doesn't even come close in terms of number of cases diagnosed to breast and prostate or lung for that matter but per case diagnosed the likelihood that it's going to be fatal ultimately is inordinately high that's a prognostic issue those are aggressive cancers but also our therapy advances have been like really quite minimal which is to say all we've got are the what i refer to as classical chemotherapy drugs of kind of the pre two thousand era which have a modest impact at all so talking about haves and have nots pancreatic cancer unfortunately remains very much in that kind of have not end of the spectrum.

Yeah a couple other points to make just on the broad contours of cancer one of the other carcinogens we haven't really discussed which is essentially the second most prevalent environmental trigger of cancer after smoking is obesity and we can certainly debate whether it's obesity per se which i don't think it is in other words i don't think it's adiposity i think it is inflammation and growth factors that come with obesity namely insulin probably igf one not to mention the inflammation that is part and parcel with that which i assume is in some way impairing the immune system and things of that nature so that's another example where you have a lot of these cancers let's think of those top five breast prostate pancreatic are clearly linked colorectal as well i'm not sure about lung so lung might not be as related to obesity as the other four but there are also many other cancers that fall outside of the top five lethal where we do tend to see this relationship to my last count i think there are about twenty five twenty six maybe twenty seven cancers that have a pretty tight relationship to that so that's not only something that's increasing in terms of societal prevalence but you might argue that that also takes a while to sort.

Of kick in yeah totally right thank you for inserting that because it really is it's so easy to think about ultraviolet radiation and skin cancers so easy to think about smoking i mean now that we understand you know when we sequence an individual cell or a population of cancer cells sequence their genome and we can now see the footprint if you will the damage that those types of carcinogens induce obesity is unquestionably another that third highest ranking quote unquote carcinogen but the way it does it is certainly more complicated and it is as you're saying sort of it's systemic you know i really do latch on to that literature that you alluded to regarding insulin signaling the body's metabolic response to obesity i mean even you can study this just in a fed versus fasted state like in short term setting but when you're someone is obese there are metabolic adaptations if you will that the body sort of attempts to make and i would draw the analogy to you know where we started with the hormone receptor driven cancer so breast and prostate you know it's a different phenomenon to a degree but basically you know insulin growth factor igf you alluded to and then its receptors on cells which are sort of ubiquitous on all cell types and certainly the cell types that for which we've got epidemiologic evidence that those cancers are more common in the obese population you know what you can say from laboratory data is that the signaling that happens through insulin signaling in cells it's tightly tied to what we kind of talked about already which is that sort of growth factor receptor pathway it is ultimately part of that same biology there's a pathway that connects those surface receptors into cells and that then regulate how the mitochondria act as the power stations if you will inside of cells to the so called pi three kinase pathway well described as being a driver in cancer that pathway is basically being chronically driven in that setting of high insulin levels high insulin growth factor circulating levels so exactly what threshold level poses risk and over what period of time i would say those dots haven't been fully connected but the epidemiology is undeniable and i would say the laboratory data that supports that connection is also undeniable so you know there's something about that pushing that driving it's i mean like chronic inflammation as you cited which itself by the way forces a direct causal factor for certain cancers an organ site or tissue site where there's chronic inflammation well described that cancers can arise in that setting it's a similar phenomenon basically they kind of keep whipping the horse if you will in a way and cells will you know ultimately through genetic alteration still basically respond to that environmental stress and cancers ensue so i remember.

In january of two thousand i'm in my last year of medical school and i trekked across the country from california to bethesda to go and spend four months as a medical student rotating on the immunotherapy service with steve rosenberg and this was the opportunity and dream of a lifetime for me i had read his book the transformed cell many many times as a medical student and wanted to basically go and learn what i could and i look back at that i think i was there from january until april of that year i mean literally one of the most joyful examples of pure bliss i've told this story before but i think i told this story when i had him on the podcast i had found a friend i could stay with in bethesda but it turned out in the four months i was there i was probably only there eight times i didn't leave the hospital i literally had a cot where i slept and i just didn't want to be out there and i want it to be as close to the lab as close to the clinic as possible but i'll never forget one of the most insane things that he said in the first week that i was there he said looking back over the past thirty years we have basically made no progress in the long term management of metastatic epithelial cancers translating that into english if you had a solid organ tumor that had spread to a distant site in nineteen seventy the chance that you were gonna be alive in ten years was the same in the year two thousand and that was basically zero now there were a couple of small exceptions and they happen to be the cancers that you and he are both interested in there were about ten to fifteen percent of patients could achieve a solid durable remission at the time to a high dose interleukin two but that was not appearing to be the case for any other epithelial tumor and there was still absolutely no sense of why that wasn't the case for the other ninety percent of patients who had metastatic renal cell carcinoma and melanoma how are we doing today twenty three years later do you have a sense of how much bigger that number is so if we went from zero percent ten year survival in nineteen seventy and i'm using ten year to really try to get out some of the median survival extension stuff but if we were zero percent survival for solid organ tumor in nineteen seventy call it one percent in the year two thousand on the back of the few cases of rcc and melanoma what are we at today i think fifteen.

Percent is a conservative number some would make a case for twenty percent i think the problem is there that we need a little bit more time some of the newest therapies you know are.

Only we don't have the ten years.

Yeah we don't have the ten years but if you track their five year three and five year outcomes if you will you'd like to think that they're going to get us to twenty percent just to clarify what we mean by using the term metastatic so clinically overt detectable metastatic cancer means that you're picking it up radiographically or clinically that's what that term means now the fact is that cancers are found when they're found at what's thought to be an earlier localized site it's very very common that cancers will have spread to so called regional lymph nodes like through lymphatic channels to the closest lymph node basin wherever that may be this is not true for all cancers but certainly true for the common epithelial cancers you're focused on in this question basically the point to emphasize there is that spread to lymph nodes is properly called metastatic it's a jargon term we don't think about that as being metastatic sort of the analogy.

Right is like when people leave a city in an airport and go to another airport that's in another city we don't call it spread until they leave the airport and go to the city proper even though they've clearly demonstrated the capacity to go from their house to the airport hop on an airplane go to another airport and once they step foot out of customs and collect their bags well now we can say they've.

Really spread the other point i was just going to quickly make is that it's feasible to surgically remove regional lymph nodes along with the primary site of disease in the vast majority of cases and so because of that sort of historical standard practice of surgical resection including regional lymph nodes we think of surgeries that can encompass all of that as basically being one treatment and then those patients we're going to come to this i think probably a little bit further along in the conversation but they are thought to not have metastatic disease but what i mean by that is overt so like you can detect it clinically or radiographically how do we know that some of those people actually have metastatic disease at that time well by following them five and ten years well not even that long i mean one two and three years is in fact enough for most of the aggressive cancers you do the surgery you clean the slate you do scans you know of various kinds you see nothing and basically a substantial fraction of those patients depending on the cancer type and depending on how much the features of their primary tumor as well as lymph node involvement a substantial fraction of those patients let's go with thirty fifty percent kind of a typical range over those few to several years of follow up will manifest metastatic disease well they always had it they had it from before the surgery was ever done and as you said cancer cells or the analogy of the traveler left the airport they lodged in a distant site we just didn't have the methods to find it so time would tell that in fact in retrospect they had had it and this is where actually some huge advances have been made in terms of blood based detection of those instances we're not perfectly good at that now but there have been substantial improvements in the technology for detecting particularly circulating tumor dna in instances where people have only microscopic metastatic disease that's the term i wanted to kind of insert in this conversation is microscopic metastatic disease we'll come back to this but let me just pick up on this theme again for evident overt metastatic disease when you can see it on scans or clinically witness it that's where those numbers pertain that we're talking about like getting in this fifteen moving towards twenty percent range ten percent on an absolute scale let's go with the idea that we're on the path with available therapies that have just recently been introduced included towards that twenty percent number half of that advance has come from one therapeutic modality pd one antibody based immunotherapy a single approach has accounted for half that number it's astounding and then what about the other half that has come from a repertoire of these so called molecularly targeted therapies that intercept those genetically altered drivers that i alluded to some minutes ago these surface receptors and their downstream signaling molecules those individual drugs have picked off as small as zero point two percent of the cancer population in the rarest instance up to a couple few percent but you add them all up and those have produced also long term survivors now by historical standards so that ten year number is an astoundingly long survival by historical standards because metastatic cancer will prove fatal in nearly everybody untreated within that timeframe even the most indolent cancers.

Yeah so let's just kind of go back and restate the important part of that so basically nineteen seventy to the year two thousand zero progress has been made two thousand until now we've probably been able to make a small dent in that half of that dent has been on the back of keytruda how many drugs are in the other half of that so we mentioned gleevac a minute ago that was probably the first.

There have been fifty two fda approvals but that's against nineteen unique mechanisms right so there's a lot of meat to ism i mean this is true in all therapeutics not just oncology i tend to then go down to that number nineteen unique mechanisms and even there there's some overlap so like different molecular targets but like for the same population like within a given pathway inside a cell there's instances where we've actually successfully drugged one component and its immediate downstream component and the immediate downstream component yet again that would then count as three on that list of nineteen but really they're very overlapping so if i were to really boil it down we're kind of in the ten range in terms of you know truly unique molecular targets and keytruda does have company so this target of keytruda just for those who are trying to keep up with the jargon as they do their google searching on any of these topics the target of keytruda is capital p capital d hyphen one that's a surface receptor on certain immune cells particularly on these cd eight positive t lymphocytes that can kill tumors directly but there are other immune cells that express pd one and that's a break on those immune cells so the antibodies that block that break are the so called pd one antibodies there are five of them that are fda approved and keytruda or pembrolizumab is that's the dominant one that made it to market first and also in the broadest number of cancer populations when i said me too ism before there's lots of me tooism in that space and then is.

Anti ctla four still being used or is that mostly just being used in melanoma what's the prevalence of its susceptibility versus that of pd one four cancer.

Types now and most would argue a fifth have evidence that adding ctla four to pd one as another block so that's another break on the immune cells on the same t cells it was actually discovered before pd one as a target and the therapy was advanced against it a little earlier than pd one but a much smaller percentage of cancer patients get a benefit from that drug there's some evidence that it actually can act kind of independently sort of exert its own benefit but i'm ascribing that ten percent number by the way there's some real math behind that it's not totally like just a gestalt number of patients who get long term benefit from pd one if you add in ctla four you're in the one percent range in terms of the addressable population for ttla four antibody therapy who derive then ten year type benefit so pd one is doing really the heavy lifting i.

Think it's probably worth just sort of explaining immunotherapy again we have an entire podcast dedicated to that when i sat down with steve rosenberg you and i spoke about it briefly four years ago but i think given that the immune system is i was about to make a joke that wasn't intended to be a joke i was about to say it's not innate as in our understanding but of course it is innate in its physiology but given that i think that people don't necessarily completely understand the nuances of the immune system given that it's played such an important role in cancer optimism over the past two decades and given that it's probably about to play more of an important role as we go forward i think it's worthwhile for the listener and viewer to understand how the immune system works with respect to cancer because when we talk about til when we talk about checkpoint inhibitors which we've already touched on i don't want people to be lost so unfortunately this is one of those moments in this podcast where you gotta buckle your seatbelt up a little bit but it pays dividends because you become a very educated consumer of how these drugs work.

Let me kind of layer the onion this way which is i find it most useful and i'd say this even in talking to patients my lay audience if you will to start with the concept that the immune system needs to find levers that it can grab onto as in differences things that are fundamentally different than normal cells our immune system is trained in fetal development to do exactly that and quote unquote only that except for the fact that we unfortunately hold on to self recognizing immune cells and those can cause autoimmune disease which is not the topic of our conversation today but basically consider what's different about cancer cells you know what have we learned over the decades on that topic there are a variety of differences i'm going to start here because it's kind of gives a little bit of chronology in a way we began to understand some time ago that a common feature of cancer cells is that they behave like their sort of progenitors or precursors like in development all mature cells in the body come from a a stem cell of some sort and there's lineage and different lineages and different types of stem cells but ultimately you see cancers actually adopt sort of a biological behavior that's like backing up if you will in the developmental process this is just a consequence of the genetic alterations sort of the combination lock as i often refer to it of genetic alterations that can lead to cancer that's one of the programs that they typically adopt and it turns out that developmental cells have surface proteins surface markers if you will that are not expressed in fully mature tissues and the immune system can see those that's well documented and steve rosenberg's early successes actually were identifying those immune cells that existed in people that could recognize those types of antigens these are referred to as cancer testis antigens so just think of that as kind of this developmental sort of biology turns out there are also interestingly some what we refer to as lineage antigens so like surface markers that tag a certain cell type that the immune system interestingly can recognize even though we think of those as being more like self but we see that we see evidence that the immune system reacts to those and that there are cell therapies as you were alluding to before that also take advantage of that the big discoveries of the recent several years have been that carcinogens cause mutations in genes that then those genes encode first rna and then proteins and the altered amino acid sequence of the protein that can be recognized so those are intracellular almost always those proteins but we have a machinery in our cells all cells in the body including those cells that go on to become cancer that basically breaks down those proteins as they age and will present a representative set if you will of those broken down protein fragments or peptides to present them meaning on the cell surface in the context of these molecules we refer to as major histocompatibility receptors as they're kind of alluded to but the idea is that show the wears if you will the inner contents of a cell to the immune system because we think that because of that that virally infected cells have an infection inside we think this is how this machinery was ever you know how it ever evolved in the first place and so kind of showing the inner contents if you will as a way of being able to let the immune system know that there's a virally infected cell well that same machinery exists again in every cell and by the way if cells stop doing that there's a branch of the immune system stops presenting antigens at all antigen is a new word i meant to introduce that antigen means a difference like a protein fragment that's being presented and seen as different we call that an antigen and it can come in these different categories that i'm talking about so basically if a cell if a cancer cell were trying to hide itself if you will by not expressing these receptors to present antigens then there's actually a branch of the immune system that's basically natural killer cells as they're called they're very primordial immune cells that are supposed to just swoop in and kill those cells and we have evidence that.

That does occur so let's just pause here keith to make sure people are following the anthropomology of this basically you have a row of homes and each person in their home is responsible for demonstrating the contents of their home so they reach inside and they pull out various items from their home and they leave them on the curb and the military is coming down the street inspecting the contents on the curb and they're just making sure that it's all stuff that we've pre agreed is safe right so they don't know the entire repertoire of what could be presented but they have a very clear list of what is acceptable and they're basically just identifying anything that is not on the acceptable list and if anything shows up and it's not on the acceptable list the house is destroyed furthermore if you leave nothing on your curb either because you're too incompetent or you're nefarious and you're trying to hide what's in your home there's another branch of the military that comes along and just blows up your house so failing to play the game results in a loss of home that's.

Right well said so that's the beginning i mean it's this kind of sampling if you will like you said of the inner contents that's important to recognize because if you start with this core principle that cancer is a quote unquote genetic disease meaning that mutations that happen in key genes that disable cells ability to repair dna damage as a common feature of cancers for example or mutations that activate some of those surface receptors or downstream signaling molecules that we talked about before those mutations we've learned in recent years can be seen as different so they began to increase the toolbox if you will of handles that the immune system can latch onto so if you think about it that way cancers begin to form potentially if they're witnessed by the immune cells as having a difference early we have lots of evidence that they can be eliminated and there's actually indirect negative evidence if you will that people who have profoundly compromised immune systems will pop up with cancers i mean if you give people seriously high dose immunosuppressive medication for various other medical conditions you will see cancers just sprout up quickly and then certainly over time as well this immune surveillance concept is an inordinate amount of evidence in support of this idea that if at least keeping them you proto cancers down if not outright eliminating them is that's just part of life on planet earth in the cosmic storm if you will with uv radiation as being one carcinogen i mentioned well actually gamma radiation coming through the atmosphere is also a cause of dna damage we have to try to repair that damage inside of cells i mean when i say we again using the anthropomorphic inside of a cell's inner workings here but if the repair can't happen we have this other mechanism of immune surveillance basically to wipe it out the reason why i wanted to just kind of spend enough words on this concept is that basically people have to understand that by the time they're diagnosed with something's gone wrong the system didn't work to detect in this surveillance mode the forming cancer it didn't eliminate it how can that be well it turns out for every process that activates the immune system in response to an infection just go with the idea that that's the primary function of the immune system in terms of how it is that we ever got out of the swamp in the first place evolutionarily there's a break on the immune system you can't just elaborate immune response indefinitely i mean imagine having the flu forever like just dumping cytokines immune system hormones into the bloodstream cranking up body temperature consuming a ton of metabolic resources in fighting infection and feeling bad as a consequence when you have the flu you can't do that indefinitely you got to stop immune responses and so we have mechanisms to do that turns out very elaborate set of mechanisms to do that and cancers have just ever so craftily figured out how to basically kind of reach into the genetic code the blueprint and co op mechanisms that will basically impede immune system recognition and response that's the pd one pd l one story so pd one we've talked about that's the target of keytruda but what cancers do it's a nasty little trick is they've figured out how to not all cancers but the ones that are most responsive to keytruda they have figured out how to express on their surface the foot depresses on the brake okay so that's called pd l one so programmed death l one ligand one which basically reaches across to pd one on t cells and tells them shut down basically mission accomplished don't need to do anything here and so a lung cell an alveolar lung cell that ultimately becomes cancer is not supposed to be expressing that protein on its surface right it's not supposed to be regulating the immune system that's not the natural job of a lung alveolar cell but a cancer that arises from that cell in many instances basically figures out how to express that protein and so then blocking the interaction of the foot with the brake that's the magic there it is now that's just one mechanism but as i said it's actually produced a bigger incremental benefit in the cancer population than any single mechanism we've ever discovered in all of cancer biology research and therapeutic development history so it's a pretty powerful one but i'll just conclude with this statement that there are other mechanisms by which the immune system can be suppressed in fact there's entire cell types in the immune system repertoire have a dampening effect on immune system response and cancers can recruit them into their so called microenvironment and create this very adverse environment for the t cells that could otherwise attack and kill so it's like almost like assembling a force field by virtue of inviting in these non cancerous cells this is like the cancer cells recruiting in these suppressive immune cells so this is some of what we're up against i mean i just want to make it clear how kind of complicated it is yes we're super grateful to have had this kind of eureka moment with the success of pd one drugs but cancers have co opted multiple mechanisms by which they defend themselves in terms of trying to close the gap then and use this immunotherapy concept much more broadly in cancer is going to require us to develop the understanding of okay well which tricks are being pulled and how to be able to really target those very specifically we can't disable people's immune systems that's not okay and so we do need a fair amount of precision and figuring out kind of the sweet spot if you will in terms of what mechanisms cancers are using for this purpose all the things.

That steve talked about when i interviewed him last year the one that i was most blown away by which spoke to my time away from the trenches time away from what you're doing day to day was that roughly eighty percent of epithelial tumors had novel neoantigens now again if you said that at a party that would go over everybody's head and it wouldn't resonate as a particularly insightful thing to say but in light of what you've just said let's make sure people understand what that means and how shocking that is relative to where we were twenty years ago just to put this in context when i finished my time at the nci and went back to finish medical school and applied to residency you know you talk in residency interviews you're talking about what you're obsessed with and what you're interested in and i talked a lot i mean that my time at nih was such a formative part of my education and i can't tell you how many people i interviewed with that just laughed in my face and said this immunotherapy stuff is nonsense like it's totally irrelevant what are you talking about kid like you're going to sell yourself to us as an interesting person that we should let into our program and you're talking about that crap like it literally means nothing okay it works on melanoma who cares okay why is the fact that eighty percent of epithelial cancers have novel neoantigens a totally staggering feature that had people understood that twenty years ago maybe more than just a handful of people would have found immunotherapy to be a very.

Promising field let's break that down a little bit you know kind of the biology behind this so mutations accumulate in a cell that's going to become cancer fair number i mean we're talking you know never less than dozens in the quote unquote most genetically simple cancers but you're typically into the hundreds and thousands and basically not all of those have a consequence to the point about these antigens so some of them are in parts of the genome that don't even encode proteins in which case they're not going to ever become the types of antigens you're alluding to the ones that are translated into proteins again those proteins age they get broken up in the proteasome presented in the context of these mhc molecules that i referred to before on the cell surface but that's done differently in each of us and so basically we don't show our entire wares we show selected representation of them in other words these mhc molecules you inherit kind of half of your set from your mother and half of your set for your father they have a ability to grab just certain protein fragments and present them when i say grab they're like actually loaded onto those by a cellular machinery that's quite elegant and so the point is we have this repertoire of showing the inner contents and so only certain mutated genes that translate into let's call them mutated proteins or altered proteins only certain of those can actually be presented out of the very large number of mutations that actually exist but what is astounding is that as you say eighty percent of so when you use epithelial cancers just remind people like breast colon prostate lung it's not leukemia and lymphoma and brain tumors right yeah not leukemia lymphoma or brain tumors and melanomas we mentioned before this actually come from melanocytes which are of neural crest origin which are actually share common features with brain tumors but basically just to be complete it's all the rest of cancer what's astounding is that basically you can find evidence that these mutated proteins are being presented in the vast majority of these common cancers and here's the point we are born with well born and during early development after birth we elaborate this very impressive repertoire of t cell receptors that sit on the surface of t cells that can recognize exactly these altered proteins like with just one amino acid substitution present in the peptide fragment we've got that repertoire the proof that these antigens are antigens i mean to meet the definition of antigen you have to find in a human being that the immune system can actually see it in the context of it being presented on these mhc complexes and turns out that it's kind of a lock and key concept essentially it has to structurally work out that the protein fragment is being presented in the t cell receptor docking in and seeing that version but not the unmutated version where that difference is enough to basically tell the t cell go kill yeah so these exist this first began to be described in earnest about a decade ago you know of course we were sequencing cancer genomes a ton at the time and we figured out as pd one and ctla four were being clinically developed we began looking then in retrospect and seeing you know it's these tumors that have a ton of these mutations they're the ones that are responding like much more likely than other cancer patients slash cancer types and so guess what it's the ultraviolet radiation associated cancers that have like just enormous amounts of mutations in total and the presence of actually significant numbers usually oftentimes dozens of these mutated neoantigens that's the jargon term that we're coming towards here and so that explains why the response rates are so high in those cancers smoking related cancers then account for just about all the rest of where pd one has been efficacious like we didn't know this when pd one and c twelve four antibodies were first being developed that it was this interplay that we could then just add one drug that blocks this foot on the brake as i mentioned before and bam you unleash these pre existing t cells against these presented antigens but that does explain a ton of the benefit that we've covered already with this so called immune checkpoint antibody approach so that's fascinating i think what you're coming to is then what else can we do with that information and so what steve i'm sure talked about with you is well we can actually engineer immune cells to attack these things basically potentially overwhelm other ways that the immune system that cancers try to protect themselves from the immune system which is what cell therapy of various kinds can do so basically we're still in the early days of elaborating this understanding that yes the vast majority of cancers have these alterations that the immune system can actually recognize let me just finish with this one very nuanced point we have learned that some mutated new antigens will cause a much more robust immune response than others in other words they're not all the same in terms of the sort of type of immune response that can be elicited and there's an argument that many have made in terms of thinking about cancer biology and evolution and coexistence of this immune surveillance system that basically the mutations that we end up seeing in diagnosed cancers are ones that aren't particularly well recognized they don't produce powerful immune responses the ones that produce powerful immune responses well guess what those cancers never became cancers in the first place they got wiped out so there's this notion that like basically you have to be able to fly under the radar you can build yourself as a cancer cell with a certain repertoire of mutations provided that none of them are powerfully immunogenic we could.

Talk about this forever i'll say a couple more things on it so that we can move on to talk about t cell therapies where i think we're going next again i think to put a bow on this the way i think about this is that through all of recorded human history there have been very very rare reportable incidence of spontaneous regressions of solid organ metastatic you know these epithelial tumors right where you know steve rosenberg writes about one which was the patient who got him to completely change his career it's the nineteen sixties he's a resident at the brigham a patient comes in who ten years earlier had been sent home to die with metastatic gastric cancer throughout his liver you know they took his stomach out to palliate him and he should have been gone in three months he shows up ten years later with a gallbladder that needs removing not a shred of cancer clearly a spontaneous remission there's an example of someone who made not so much and so significant of an antigen that it got wiped out before it got anywhere this one actually got all the way to the promised land but somehow at that point the immune system said i recognize it and there are enough of us that recognize it and we're going to wipe this thing out and then what basically happened and it took twenty years yeah almost twenty years right was figuring out that if you just dump enough interleukin two which is candy to t cells you're going to pick up the next threshold which is in melanoma in renal cell at the time we didn't know why but as you point out they just have so many freaking mutations that you're bound to just stoichiometrically come up with an antigen that's going to be your lottery ticket just dump enough interleukin two on we're going to flip the next threshold and then of course the checkpoint inhibitor takes it one step beyond that which is okay you clearly don't have enough from spontaneous mutation spontaneous response you don't even have enough that if i just gave you il two but if i give you a more sophisticated help turning down the suppressor now it's going to work but to really unlock this to basically say we could make eighty percent of cancer gone just gone imagine that and by the way it might be more because maybe you can induce mutations we're going to come to that in a moment if we just wanted to take eighty percent of cancer deaths off the table we have to be able to find out who is that perfect soldier down there that's really really really outnumbered and make more of them so what does.

That look like just to connect the dots from early versions of cell therapy to where we are now steve rosenberg's work was so called adoptive t cell therapy let's not focus on that jargon term so much but basically doing a surgery to remove a single site of cancer metastatic cancer removing the immune cells that had found their way into that cancer which turns out actually some of them are seeing antigens they're specific for others are just trafficking through and they're kind of bystanders as it turns out but any case immune cells don't traffic in high numbers through all cancers but certain quote unquote immunogenic cancers yes they do melanoma again being near the top of the chart there what steve was doing through the nineties and certainly by the time you got there was taking those immune cells isolating them from that patient's tumor and simply expanding them no.

Genetic anything it was just grow these.

Till exactly yeah to a number that when he infused them back could then you know systemically could then traffic through the body and destroy people's cancers now not all the time but a significant minority of patients could be cured that way that's still true today and by the way we are right on the verge of that just that approach alone no genetic manipulation becoming an fda approved therapy finally for melanoma which is where steve had had the most consistent success back in those years he's tried it in many different cancer types what's been learned along the way is exactly what we've already summarized which is you know this idea of antigen specificity that you can find you know this kind of what is it that the immune system is seeing these infiltrating immune cells in tumors what are they looking at and then taking that knowledge to basically now begin to engineer immune cells generally starting with the patient's own immune cells so not coming from tumor anymore but just basically collecting them from the blood you need a fair number of them but because of genetic engineering advances cellular genetic engineering advances we can now basically swap in swap out essentially whatever we like and in these immune cells that we want to direct against cancers we can basically introduce the recognizing piece if you will if we sequence a patient's cancer which we do as part of routine standard of care these days but you do it a little bit deeper a little bit more in a systematic thorough way basically let's go with that number eighty percent of patients we can identify a mutated antigen that will only be in the cancer cells and introduce into their immune cells a surface recognizer if you will i'm just being vague about the determine to not get lost in too much jargon all at once and then basically just dial up that number of cells in the laboratory and then infuse them back like a blood infusion which is how cell therapy is given and that's the approach that translates you know connects the dots that we've covered we are not doing that today to be very clear the cell therapy advances beyond just simply expanding the tumor infiltrating immune cells or lymphocytes beyond that approach the engineering that's being done right now are against surface lineage markers so on b cells for lymphoma primarily but some leukemias and now multiple myeloma as well basically we are wiping out the cancer cells that arise from that population and the normal ones okay just to be clear what we were talking about is a very elegant very tumor specific cell therapy strategy which you can readily envision sort of taking the field if you will but where we are right now in cell engineering is going after common surface markers in cell populations that we can quote unquote afford to get rid of so eliminating b cells is actually not a great long term thing but you can actually survive without your b cells these are antibody producing cells for those who don't track immunology so the.

Poster child for this of course is cd nineteen and as you said every b cell is walking around with this marker on it we don't have to get into why it's called cd nineteen and when a subset of b cells go on to become lymphoma that is otherwise unresponsive to other treatments lo and behold you could wipe out you could basically send in someone that's going to target every cd nineteen you'll get rid of the bad guys you'll get rid of some good guys on balance it's worth it for sure but yes what we're talking about here is a next layer of sophistication because for example if a patient has metastatic lung cancer it's not an option to wipe out all of the lungs but it's also a more complicated problem like there are many cancers for which you could completely live without the organ you don't need your colon you don't need your breast you don't need your prostate you don't even need your pancreas i mean i'll give you an example i think you may remember this i have a friend with lynch syndrome it was unbeknownst to him because he was adopted developed colon cancer in midlife again a great surprise when you're forty to develop a stage three colon cancer but later developed a pancreatic adenocarcinoma i sent him to see an excellent doc who i had trained with and he was inoperable so everybody who is familiar with pancreatic cancer understands inoperable locally advanced pancreatic cancer is a six to twelve month prognosis but because he had lynch and this was twenty twelve maybe maybe twenty thirteen it was just around the time that a paper had come out in the new england journal of medicine that had mentioned hey if you have mismatched mutation genes you might be a candidate for this new anti pd one and this story has a happy ending in that sure enough he got the ntpd one went into a complete remission but now needs insulin because his immune cells destroyed every pancreatic cell in his body not just the cancer but the non cancer do we not have enough novel proteins on breast cells or prostate cells that the cd nineteen approach is going to work anywhere else is that a one hit wonder well.

I wouldn't say that but it's true that we're you know these t cells are so powerful you need to find handles again on the surface that are truly specific for cancer cells so i was honing in on what is truly specific for cancer cells these mutations it's a big hill to climb that we haven't gotten into in terms of developing personalized engineered t cell therapy for the entire global cancer population there's a cost issue there there's a technology issue to some degree as well but any case in the meantime what is the field focused on right now it's trying to identify those surface markers proteins that are truly specific to cancer and that's what we've been struggling with because there are other therapeutic modalities that don't require quite as much specificity like you can direct chemo even you know an antibody that's on the back end of it has chemotherapy drugs that get sort of ingested by the cancer cell and have a more localized effect radionuclide so like really powerful radiation emitters on the back end of such molecules also and it's clear you know clinical data and now some approved drugs even that are what i'm describing that there's like a spectrum of selective expression that is not needed there but for cell therapy you need it otherwise again you're going to obliterate every single cell in the body and here's the problem cancers come from us when they're reading the blueprint if you will and translating certain genes into rna and then proteins that comes from the same genetic blueprint that our normal cells have and so finding such proteins this has been a real such as technology gap but it's been a real conundrum and feeling blindly and just trying a bunch of things because of the power of the killing potential of these immune cells there's every constituent in the field has no appetite for that this has been where the field has been anguishing most in terms of trying to understand if there's more cd nineteen like opportunities but on common epithelial cells where we can't destroy the normal version we need to get to this greater specificity let me just insert one final thought here which is that the cell engineering field has certainly advanced to the point of being able to create bifunctional recognizing elements so these surface recognizing receptors where basically both of the targets have to be present so like an and switch as it's called like the boolean and or instead of just creating a cell that goes after cd nineteen you create a cell that goes after cd nineteen and cd twenty and you only ever kill a cell that's got both actually that's not a perfect example because cd nineteen and cd twenty are almost always co expressed on b cells but any case you get my point that there is a fair amount of work going on right now to try to find pairs of proteins that might only be expressed on certain cancers that might start to give us the opportunity to take this same basic approach that's more readily scalable than the more personalized while you've got this genetic makeup of your cancer cells and we're going to zero in on a personalized approach that's specific to your immune system type and to that mutation in theory it can be done but we have to drive down cost of manufacturer we have to allot lot has to happen for that to be remotely feasible economically manageable let's go back to til.

For a moment you mentioned that they're on the cusp of receiving an fda approval for the treatment of metastatic melanoma so again just to bring people back to what that means that means a patient with metastatic melanoma who presumably has progressed through all other non cell therapies and still has harvestable tumor this is a very important feature of till you actually have to be able to surgically pull out a large enough sample of a tumor so a patient for example has cancer that has spread to their lung they have to actually undergo lung surgery and take out a wedge or lobe or whatever amount is necessary that tumor is taken immediately to the lab where all the lymphocytes that are there are expanded and expanded and expanded and i forget so long since i've been at it i think they want to get to at least ten to the nine is that the order of magnitude okay you expand this to about ten to the nine cells and they're re infused usually with interleukin and again you're looking for this response it sounds great in theory why doesn't it work every single time you've clearly identified lymphocytes that know how to go there and presumably that's half the battle why doesn't this.

Work every single time again it goes back to defense mechanisms to a degree i mean it's i talked about that kind of layering of the onion metaphor before or layers of force fields it is the case that there's actually direct mechanisms that can impede killing at the tumor cell level and i talked about like pd l one being expressed on cancer cell surface well it turns out even intracellular mechanisms so the way in which interferon which is an immune system hormone that basically triggers cell death it's part of the killing process that when cda positive t cells are trying to kill a cell to a virally infected cell or in this case a cancer cell and it turns out that to become cancers successfully become cancers in the first place that you can find direct evidence certainly in melanoma of that cancer intracellular pathway itself being altered that the immune cells are actually unable to do the killing because that cell is no longer sort of sensitive to immune cell mediated death which is a very nasty little trick and one that can't be overcome just by dumping in more immune cells at least we don't have direct evidence that it can this also can cause resistance to pd one antibodies we demonstrate it in melanoma and a handful of other cancer types now so you have to start inside the cell in terms of ways in which cancers have evolved an ability to resist immune recognition that is that they're contending with but then you've also got that recruitment of suppressive immune cells that i alluded to before which essentially very antigenic cancers very commonly do that need to do that and you can't overwhelm them just by introducing more cd eight positive t cells by and large and so in those cancer types where those so called myeloid cells are very very predominant this cell therapy has just not taken hold at all and then there are trafficking issues basically features of cancer microenvironments some of them related to oxygen tension some of them related to nutrient availability that make it very challenging for immune cells to persist multiply and do their killing work and so we've known for such a long time cancer cells are metabolically inefficient that they're living in this incredibly harsh environment as in very low oxygen gradients people didn't really understand the why of.

That what you're describing of course stems in part from the warburg effect which had always been people had always thought well it must be that cancers can't undergo oxidative phosphorylation and that's why they're doing this inefficient thing but to your point between the substrate argument going through reams of glucose leaves you more building blocks which is what they need more than atp and then on top of that you're lowering the ph you're creating this incredibly harsh microenvironment it seems like there's every reason in the world from a natural selection standpoint for cancer to.

Do that this is my point is that i think it's the why of it well cancer cells like ultimately figure out how to sufficiently thrive if you will in such harsh environments well who can't survive in that very harsh environment immune cells the idea that this is all much of this has to do with creating conditioning this harsh environment as a force field this is another thing we are not addressing by virtue of just dumping in more immune cells my argument is when i talk about multimodality therapy for cancer it's about targeting those mechanisms that we can address inside the cancer cell it's about modulating the environment metabolically actually even fixing to a degree this oxygen paucity of oxygen in the pockets of that as well as manipulating these other cell populations like immune cells and turns out even like fibroblasts for example get recruited into certain cancers most notably pancreatic cancer they seem to be part of the force field against the immune system as well so we have to kind of knock down the force field i mean it's just the star wars analogy right you've got to take out the moon that generates the force field around the death star before you send in your fighters to actually try to destroy it and so to me we're on the verge of understanding kind of the hierarchy of this biology and how to think about both diagnosing and then treating at this level but the toolbox has to elaborate much more completely it's just in my strongly held view it's not going to be four therapeutic maneuvers all in column a or four in column d it's like one from a one from b one from c one from d that's the type of four drug regimen that's going to eradicate cancer and it's not going to be one cocktail for all patients let's dig.

A little deeper into that in terms of what the next five years might hold for us right so if we're sitting down again in five years to talk about the success of the previous five years what's likely happened how much further have we gone in immunotherapy just in straight up activating t cells either through adoptive cell therapy via genetic engineering to take peripheral blood lymphocytes and turn them into or engineer them into til let's put that as a category of therapy let's talk about other ways to identify checkpoints or checkpoint inhibitors and or combat the tumor suppressor cells so call that the sort of tumor suppressing environment go after it how much of it is going to be in the metabolic environment or the interstitial microenvironment and targeting the hostility and then how much of it is going to be inducing mutagenesis so again you and i spoke about this probably a couple of years ago and i ended up i think i was able to keep it in the book i know there's always so much pressure you're trying to chop stuff out of the book so i don't remember if this finally made it in but i at least referenced one study that had taken patients i think with lung cancer none of them had any pd one activity and then a course of platinum based chemotherapy all of a sudden rendered a subset of them to now be susceptible to it in other words using a conventional chemo increased immunosusceptibility even though the conventional chemo itself wasn't particularly responsive and again there's lots of ways to go about doing that paradoxically you could almost imagine taking a cancer cell and exposing it to more mutation forming insult and again i'm sure there's other ideas but keeping the timeframe short which is five years what are we going to need to do to double the response rate the durable response rate within.

A five year horizon i think let's look backwards briefly over the past eight years we have exhaustively tried to find other gas pedals and brakes on immune cells cda positive t cells most notably and we know what those gas pedals and breaks are on those cells and we have tried drugging those typically on top of pd one antibody therapy and that has almost completely systematically failed now it doesn't interestingly produce horrific toxicity in other words the immune system doesn't get so hyperactivated like that's not the problem but it just hasn't moved the needle now i will caveat that by saying that those approaches have been used without any notion of trying to like zero in on individual patients and sets of patients for whom you know that that new immunologic mechanism was hypothesized to be uniquely suited in other words we've been throwing a lot of spaghetti at the wall and hoping things would stick by just treating a broad array of different cancer patients with absolutely no molecular selection even though there are certainly there were and remain hypotheses along those lines that were never really tested so anyway just trying to hyperactivate t cells with drugs i would say we've kind of played that out and it's hard to imagine the only way to revolutionize that would be what i just alluded to which is really tightening or sharpening our lens if you will and focusing on applying those drugs in very specific patient populations beyond that there's what i would say a related class of therapies the metabolism targeted therapies and epigenetic targeted therapies which have been exploding in terms of understanding how the blueprint the genetic blueprint is sort of folded up and unfolded the regulators of that and the way in which cancers many cancers like need to figure out how to co opt or take over the function of some of those folders and unfolders and so there's been a real explosion in novel very early in development drugs in that class and it turns out interestingly that altered metabolism so the warburg phenomenon that you alluded to and the regulators of that switch those have become elucidated in a much more complete way in fairly recent years many people would have thought well you can't target metabolism and get away with that because every cell in the body needs to be able to regulate its metabolism in a kind of condition dependent way that's true but cancers really do they very much depend on this metabolic dysregulation and we think that we're on to some of the unique regulators that cancers particularly co opt i would pay a ton of attention i mean our group our therapeutic development work is really quite focused in that area can.

You give us a bit more of a sense keith of what that looks like so we know that just from a glycolysis standpoint we know cancer basically is a one trick pony most cancers right they're turning glucose into pyruvate all day every day independent of how much fatty acid is available and independent of how much oxygen is available and they have perfectly healthy mitochondria people used to hypothesize the mitochondria were defective that's why they were doing it no evidence that that's the case so let's just play out what you're saying you could take something really draconian and say okay there's an end so we're not going to interfere with any enzyme that turns glucose into pyruvate that would be a bad idea because you have to do that if you're healthy so where else could you target where you disproportionately hurt a cancer cell without hurting a non cancer cell that's undergoing glycolysis our group just.

Published a paper on this topic just five months ago looking quite broadly to understand these metabolic regulators and which ones cancers seem to selectively use and interestingly this analysis was focused on immune cell recognition versus lack of recognition kind of the interplay between these two things so we already laid out the argument of the idea that cancers it seems in part adopt this inefficient metabolic strategy because it allows them to kind of suck in available nutrients and keep them away even from immune cells so we were trying to unpack that and basically when you look in an unbiased way at all of the gene products that are expressed in cancer cells differently than normal cells what you see is that it's outside the mitochondria so inside the mitochondria i'm one hundred percent with you basically you can't poison that that the factory in that way but it turns out that not only the function of mitochondria but also just like the production of mitochondria so mitochondrial biogenesis it's called like there's many different mitochondria or many mitochondria per cell different cell types need different numbers of them based on their metabolic demands so cancer cells will actually regulate the amount of mitochondria they have through these outside of mitochondria programs if you will transcription vectors in many case that regulate the program in the genome this is the nuclear genome not the mitochondrial genome that regulate this process there's some switches there and one of those switches basically jumped out of this analysis as the top differentiator if you will expressed in cancers and not in others now the type of molecule that historically has been thought to be challenging to create a drug against there actually is a proto drug against it that's still preclinical but moving forward we've been collaborating academically with that company and so early days in terms of knowing whether this is really going to bear out but these are the types of insights we just didn't have five and certainly ten years ago that there might be ways to actually kind of laser in on the regulators of metabolism that cancers are most potentially vulnerable to and i'm not suggesting these are going to be standalone approaches as i said before it's rather than a potent yeah they're going to potentiate these other therapies and let me just kind of make this statement to that point when we look at what drives resistance to both targeted therapy so those molecules i referred to before these surface receptor and downstream molecules that have been successful and extend people's lives with cancer and immunotherapy and we look at common themes in terms of resistance this metabolic switch like using oxidative phosphorylation when they weren't using it before that's a very common theme in what we call the persister cell population in both therapy types and so the idea that you would then potentiate simply what we've already got with this class of therapies go from twenty percent of cancer patients having long term survival to forty percent i'm just making that number up just by figuring out this piece of the puzzle i think that's very much in view now we might have to toggle upstream downstream like play with where it is that we're ultimately poisoning this process and we may have to do it just periodically like in other words not constant like drug exposure all the time to be able to get away with it which is a common theme in terms of thinking about four drug regimens for cancer but let's come to your idea of actually taking advantage of this very delicate balance if you will where cancer cells have accumulated genetic alterations to a degree that's supposed to be intolerable for a cell's survival in other words if you can't repair mutations and alterations that have been caused let's say by acute exposure to something like radiation for example where you get a lot of mutations all at once we have repair mechanisms but if they don't do their job then the cell basically has a program by which it's commits suicide so called programmed cell death and basically cancer cells live dangerously on the edge if you will in having accumulated these mutations in certain cancers like with your friend with lynch i mean wow the number of mutations accumulate because of the defective machinery is just off the charts like ultraviolet radiation associated skin cancers also off the charts any case the point is that we know that actually if you introduce more mutations into those cells like in the laboratory like you push them over the edge there's a limit to how much to what they can handle so how about combining that concept with what we were talking about before immune system recognition of mutated proteins and just say hey okay you want mutations again going back to my anthropomorphic now we're talking to the cancer cell you want lots of mutations because it helps you dial the combination lock if you will and become a cancer fine you know we're going to not just double we're going to ten x the number of mutations you have both to increase immune recognition and possibly also just simply push drive you towards death yeah that concept is behind platinum based chemotherapy's effectiveness in cancers that are somewhat deficient in repairing their genomes so that's a link that we've known about now therapeutically for a number of years parp inhibitors that's a dna damage repair enzyme parp and inhibiting its function can push certain cancers that are close to the edge if you will over the edge of so there's already some direct evidence that we can get that benefit the immunologic piece that requires another layer of complexity which is that basically you would need to introduce the mutations and ones that are shared across the whole population of cancer cells and if not the whole then nearly the whole so the immune system actually interestingly is able to elaborate immune responses that become broader right so this is sort of epitope spreading as it's called where the immune system latches onto a certain antigen in mounting an initial immune response but then actually can can bring in reinforcements that are recognizing other antigens and create a more sort of polyclonal response what was initially a monoclonal response so that's part of innate immune function but there's pretty good experimental evidence that you have to start with something that's at least shared in ninety five ninety eight maybe even ninety nine percent of cancer cells so this is where the idea of using let's say radiation to treat a single site of metastatic cancer in someone who's got twenty sites we've tried this it hasn't worked or very sporadic cases where actually can trigger a much more profound immune response that's actually systemic like that goes after all the tumor sites but that's quite rare again just for.

Folks to make sure we're following the reason it would be rare is if you only introduce a whole bunch of mutations to ten percent of the tumor you might generate a new immune response you might kick the tumor over the edge either by having so many mutations that it all undergoes programmed cell death or it now finally rises to the level of detection but that's not sufficient enough across the entire organism yeah it.

Won'T clear the rest of the tumors then being medical oncologist you can imagine this is where my mind commonly goes in that we have to come up with a systemic approach there's some really fascinating data that a colleague of mine at mass general is about to publish and it would suggest that basically you can incubate cancer cells and by incubate i mean actually in living beings with mutation inducing drugs aka chemotherapy drugs certain chemotherapy drugs but for that to work you need to actually be you have to kind of pin them down with another therapy first so some of the therapies we've talked about already that like actually are effective partially effective for a period of time months to many months in some cases before resistance might manifest to some of these targeted therapy approaches if you pin them down with that therapy and incubate in you know these chemotherapy drugs that basically start to dial in more and more mutations at least in mouse models it would appear that actually you can buy the time that you need to be able to actually introduce new mutations and have that trigger immune recognition and make even you know pd one antibody based therapy much more effective so we're going to try that idea in human beings basically taking so called oncogene targeted therapy backbone treatments and then using what are called alkylating agent chemotherapies which are the ones that can introduce new mutations most commonly and even at somewhat low doses it would appear you potentially can introduce the mutations without having some of the deleterious effects that chemotherapy drugs are well known to cause.

Keith i'm going to change gears for a moment only because i know we have a very short clock today relative to how long you and i could normally speak and i want to talk about another very important topic so to introduce it let me share with you some stats that you know better than i do but i'll let you interpret the stats for the listener if you take a person with stage three colon cancer so this person has cancer in their colon it's even spread to the lymph nodes of the colon but to the visible eye it has spread no further and to there's no radiographic evidence that it's anywhere else you're going to put that patient on a fancy regimen of chemotherapy i don't have to spell out folfox and all that stuff but there's a regimen of chemotherapy you'd put that patient on how many of those patients are gonna be alive in five years sixty seventy percent of them yeah.

That'S about right again all depends on the size of the initial tumor and other features but that's about right yeah.

Let'S now take that same patient in a way except he also has cancer that has spread to his liver so you're gonna go ahead and cut the colon out take those lymph nodes out but on the ct scan you're gonna notice that he's also got metastatic cancer so one of them is stage three one of them is stage four we're gonna give that stage four patient the same chemotherapy we're gonna give them the same drugs but in five years somewhere between none and a few percent of those patients will be alive and if you wait to ten years it's none what's a decent explanation for that observation which by the way if we had more time we could tell the same story for every cancer basically in other.

Words what i refer to as microscopic residual disease why is it that we're actually able to eradicate microbiology microscopic residual disease with the same drugs that don't do the job when you have macro disease yeah yeah like i was gonna.

Say in other words why does it work when you have hundreds of millions or billions of cells not all clumped together but sort of diffuse but when you have like a hundred billion cells and they're like in big visible clumps the same drugs just fail there's i.

Would say two prevailing explanations there are hypotheses i mean frankly because there'll become explanations once we actually connect the dots and really prove that we can demonstrate our knowledge by curing more patients with this so one is basically just a clonal heterogeneity concept so basically as cancers evolve we used to think that cancer cells were kind of identical clones of one another like they're just a massive number of absolutely identical cells that in the beginnings of cancer that is largely true that as cancers continue to evolve in our bodies they actually keep mutating and so you start establishing subclones you can have a dominant subclone that's typically the case like that might even be ninety nine percent of cells and then in that remaining one percent you might have ten twenty subclones we've proven now that certain therapies actually are able to pick off the ninety nine percent they leave the one percent and then somewhere in that one percent is a clone that has a resistance mutation like already in it to the drug that we're giving so there's a clonal heterogeneity hypothesis that i would say is quite strong at this point because of some of the evidence i just alluded to that that's a big part of the problem if you nip it in the bud if you will with offering the same therapy when there's not so much clonal heterogeneity that represents a curative opportunity and so when i was talking before about these so called oncogene targeted therapies which is not all of the targeted therapy successes we've had but the ones that go after these mutated activated proteins these growth factor receptors and downstream ones in particular it's very clear you can cure a trivial fraction of patients with overt metastatic disease and you can cure a pretty substantial fraction of patients in the so called adjuvant setting so microscopic residual disease setting and so we have direct evidence that this phenomenon occurs but you're asking the why question it's we think some contribution or some part explanation from having to do with lack of clonal heterogeneity the other is the secondary immune response concept right that basically all successful curative cancer therapies actually do trigger immune recognition through what's referred to as immunogenic cell death so that you're killing the cells directly with your drugs but that the mop up work if you will of actually eradicating every last single cell is the immune system's job it's a concept that was first introduced when we had just these conventional chemotherapy drugs from the nineteen hundreds and now we actually have more and more evidence that our sort of more elegant molecular targeted drugs actually engender these types of better immune system recognition phenomena as part of their mechanism of action and because we've directly demonstrated that like better immune recognition in patients who are receiving these therapies looking at biopsies compared to pre treatment and that that happens rather quickly you know i think it's reasonable to then overlay that on top and say well yeah it's extending your spontaneous remission starting point from a while ago in discussion that basically you're allowing this kind of tipping point phenomenon to occur yes you're directly killing cells with these drugs that's true but the eradication piece is ultimate in immune system phenomenon and i think there's.

Kind of a hybrid there too right keith which is that in the micro metastases environment in the adjuvant setting you have less capacity for the tumor to create the hostile environment in which to impair the immune system from mopping up the damage it all favors keeping the cancer cell on its heels and the way to do that is to just have as little of them as possible is going to increase our odds you still have to win i mean you still have to kill because if you don't it will get back onto its.

Toes that's right i mean this is what we're talking about is behind this massive wave of enthusiasm and it's legitimate enthusiasm not hype that early detection is going to allow our same toolbox of drugs to be massively more effective that's.

The only reason i posed the question you're taking the cue and you're running.

With it right we're pretty terrible at that as it stands right now many of your audience know basically we can only screen we only have real direct evidence of effective screening for a few cancer types i mean cervical cancer for sure but we could also hopefully eradicate cervical cancer by getting everybody vaccinated hpv vaccine eventually exactly but cervical cancer screening absent a vaccine is quite effective so that's one breast cancer for sure we can cut the risk of breast cancer death by about a third with mammography that's not a very inspiring number i mean i absolutely suggest that everyone who's eligible who you care about you should strongly insist that they get mammograms colonoscopy and other less invasive means of detecting colon cancer can reduce risk of colon cancer death by about twenty five to thirty percent ballpark i mean the most optimistic estimates would be about a third also and there again i'd say well that's a real number i've had my first colonoscopy and i'll keep doing them but that isn't again particularly inspiring and despite lots of effort and i'd say lots of controversy prostate cancer screening is really quite poor it's almost like just non randomly assigning people to get prostate biopsies you know getting psa tests basically it's not a great way of detecting cancers and certainly not potentially dangerous prostate.

Cancers but i would add something to that keith which is that all of those three the three last ones which are three big cancers those are three of your big five they all have something in common so if you look at mammography infrequent colonoscopy and psa i would make a case that all of those are not great screens by themselves and i'm sure you would agree so in other words people often confuse and unfortunately this is true of physicians and policymakers more than it is patients because i think the patients are looking to those of us who think about this for input patients confuse or policymakers rather and physicians confuse the statistics you rattled off as proof positive that early screening doesn't justify the cost yeah a different way to say it is no mammography used in isolation which has its blind spots is not a monotherapy psa by itself as you said is shy of a random number generator but that doesn't mean that adding ultrasound or mri to the breast surveillance program won't dramatically by stacking tests with different sensitivities and specificities right mammography exceptional for small calcified lesions works poorly in hyperglandular tissue the exact opposite is true with the mri similarly with the psa by itself virtually meaningless but that psa density psa velocity now adds much more specificity furthermore you start to add things like a four k and if the risk is high enough you get multi parametric mri i'll tell you this keith i mean i'm not telling you anything you don't know but i think again just for listeners in ten years i have not had one patient get a prostate biopsy that wasn't warranted i'm not a superstar it's not like i've got some no it's just that that we're doing this we're not just using psa sometimes we've had patients who only get picked up on psa velocity their psa is not high enough to trigger the four k no one would go and do anything based on their so i get a little frustrated when the medical community that's anti early screening or screening and early detection pooh poos it based on what i still think are impressive numbers the number you state because that's sort of like saying you know there's too many fatalities in cars we shouldn't drive right just doesn't make any sense it's like yeah there are fatalities in driving let's figure out ways to drive better you can put a seatbelt on you could not drink while driving and you could mind the speed limit that's a totally different situation than saying we're going to abandon all.

Those things so you know you're reminding me that i in my world you know being an oncologist i don't have to contend with that the community you're referring to i take those numbers as being like absolute support and endorsement but part of what i'm getting at is the remaining unmet need and it's into that massive unmet need that there has been just an enormous advance in terms of methods for detecting single alleles single fragments of genes in the bloodstream so it turns out that normal cells shed dna in the bloodstream it is digested and broken down reasonably quickly but not immediately cancer cells do this also as it turns out and the more cancer you have in your body of course the more that's not so obvious but it is true that the more cancer that is in the body the more of the copies of cancer dna that will actually be shed in the bloodstream but sequencing technologies have advanced to a degree that now from a single ten milliliter tube of blood and particularly one collected over time so kind of analogous to your psa velocity example where you're sampling at multiple time points if you sample at multiple time points now and subject those i don't mean just to the methods that are being commercialized now but are being commercialized i mean since we talked four years ago what felt like very much a research method is now emerging as a real clinical option there's methods now that can find cancers at an earlier point and a broad array of cancers like way beyond just the cancer types that we're talking about the ones for which we have screening methods i mean so really kind of almost pan cancer tests but in r and d mode right behind them are ten x one hundred x more sensitive methods that are absolutely going to move the needle in terms of our ability to find cancers at a microscopic point now here's the problem the problem is at a microscopic point what do you do where do you direct the scalpel this is a fundamental conundrum so you overlay on top of of what i just described the fact that on circulating tumor dna as it's called you can actually do more than just sequence for mutations to find that it's circulating tumor dna as opposed to normal dna you can also look at what are called methylation patterns which has to do with this kind of like folding and unfolding of the blueprint these molecular modifications that exist in certain cell types and basically if you find mutated sequence of dna and it's got the methylation pattern of a colon epithelial cell guess what cancer you probably have and while you can't direct the scalpel right away obviously you can do a colonoscopy but similarly for breast cancers and others where you can then start to focus your attention with imaging analysis to try to detect the cancer maybe not the moment that the blood test is positive maybe it's going to take you six months twelve months eighteen months of continued surveillance and then you'll find it at a much earlier point than you ever would have found it based on our other methods so that's one sort of paradigm and that's where we are right now with the adoption early adoption of methods as they exist now that are getting rapidly better in terms of increased sensitivity so there's been a real explosion in terms of investment in this area and now scale up of technologies that are commercially relevant but the other concept i wanted to just kind of weave in here is i think where you kind of started this set of questions which is that basically in certain instances we're going to find targetable mutations and by that i mean with drugs or with immunotherapies where basically you know we'd say well look we see it in the blood we actually with our best available scanning technology we can't actually see it in a way to direct a scalpel but we actually know what drug to give you to eradicate your trivial amount of cancer using the analogy that we started with here which is like clinically overt metastatic disease versus microscopic disease that remains after surgery aka adjuvant setting but now finding cancer is at a point where there's many fewer of these cells and where the defense mechanisms the force fields the heterogeneity that we talked about before don't exist and so this is i mean a real reason for optimism i should just highlight that there's two applications here one is actually to do much more precise therapy in the post surgical setting so really figuring out you know right after surgery who still has microscopic disease in them who doesn't that's a much.

Easier problem i mean i actually talked with max dean about that problem and he's one of the pioneers in that field and of course not to minimize the amazing breakthroughs there but but there you know what you're looking for you've taken out the patient's lung cancer precisely you know exactly how that lung cancer differs from a non cancer lung cell and you're out there looking and you're right i mean this now becomes the most elegant way for post treatment surveillance but it's what we started with that is the much more difficult problem and frankly the most important problem i mean if you solve this problem i don't know that the other things matter anymore oh no no if you solve this problem you win the game we've always.

Been stuck in this mode in cancer research and therapeutic development kind of start with the worst case scenario if you will right and then that's where you have to learn that's right and that the same therapies that are somewhat effective in the overt metastatic setting are much more effective in the so called adjuvant or post surgical setting and we have every reason to believe they're going to be at least as effective arguably more when we're down to two logs three logs even fewer cells at the time that we're finding and intercepting the cancer when the immune system is still quite competent is still actually doing much of.

Its job what's the state of the market today keith in terms of tests that people listening to this can actually get as part of a cancer screening protocol so grail has a commercially available kit it's not over the counter you need to get it through a physician what are some other tests out there in your view how close are we to these tests being an imperative part of cancer screening i think we're not.

Quite at the imperative point but we're certainly at the point where i would say it's reasonable to get a test if you consider yourself an early adopter and you know who you are it's reasonable to get a test and just quickly to answer your question first part of your question there's a test that was initially developed by a company called thrive that was acquired by exact they have a commercially available test as well and then another company called delphi have a commercially available test which all have performance characteristics that are in the same realm in terms of supporting their current clinical use but here's the concern that many people have which is that basically we're at a state in the field where finding people who are blood positive blood test positive could lead to a large degree of anxiety in terms of then you do standard radiographic assessment you don't find the problem and that basically the medical community because we're not talking about oncologists who are doing the tests the medical community really hasn't had time to really kind of work out the kinks of how do we manage this situation and so you can almost argue that there need to be generalists who really develop expertise content knowledge have a network of specialists that they can work with to be able to kind of catch these patients and these tests were launched before that was really created so that's just my psa here my public service announcement in terms of the fact that if you just get a test and you're not in the hands of someone who can manage a positive test that is at least anxiety provoking we've with collaborators of ours we've actually been doing direct head to head comparison analyses of how much lower can we go in terms of amount of tumor dna in the blood that can be detected with what are currently r and d methods but are readily scalable we're really at one hundred x better at that.

Point you're talking about a finger drop of blood if you're one hundred x better than ten milliliters you mean okay.

That'S true you could take it in that direction but we actually you would.

Say no stay with ten or twenty milliliters ten ml we are way more.

Sensitive yes oh exactly exactly so that's the point and then do serial analyses go with high risk populations to prove this point if you like but we can readily envision how it is that we basically start to capture you know a much bigger section of the population it's a little hard to estimate right now basically until we do more studies.

What'S differentiating these companies so if you just look at delphi and grayling so grail to me i have no interest i have no affiliation with any of these companies we use grail in our patients when we do we don't do this in everybody for exactly the reasons you've stated you gotta be able to tolerate the noise that may come of these tests that's sort of our view of aggressive cancer screening in general but when we use it we do use grail and that's largely based on the affiliation with illumina which is if you've got the best sequencing company in the world that created the engine for this thing then that sort of makes sense to me but what else differentiates these.

Companies i mean there's three kind of aspects to circulating tumor dna that we now know if you pay maximal attention to you can increase your sensitivity you can find more cancers so i started with mutations that's kind of the first principle then comes the so called fragment length so fragmentomics if you will or its own field separate from first generation genomics and that delphi basically came out of that scientific discovery that circulating t rna basically comes in different fragment sizes than normal cell dna and that basically this is a kind of population phenomenon you're measuring multiple or many many circulating dna fragments and tuning your algorithm ultimately to be able to kind of find the sweet spot of differentiation that's definitely part of the formula and i would argue that just everybody's going to rise to that inclusion of that method and then that methylation aspect that i talked about before that's the other feature that has been a differentiator in terms of kind of the of the first marketed products in this class even across these three companies but there are ten more companies coming right behind so basically the.

First one is kind of not valuable for pan screening because that's how you're checking for recurrence when you know the mutation right i mean we're not going to be able to screen people on the basis of guessing cancer mutations are.

We some would argue we can i mean as the cost of sequencing continues to nosedive believe it or not still going down lower and lower cost per unit of sequencing done there are some who argue actually no no we just go after you know pick a number you know the thousand most common cancer mutations the ten thousand most common the hundred thousand most common cancer mutations that.

We actually can yeah i mean i guess if you had kras and you had p fifty three yeah p fifty three three and yeah be rap p.

Fifty three is mutated in fifty percent of all cancers now the problem is there's hundreds of different mutations it's a big gene but still people used to object to that concept based just on a sequencing call cost argument but that i think is becoming less and less relevant so that first feature doesn't require that customization which is what's being done in the post surgical setting you alluded to that but just to make sure that people understand that that tech good point when you know what mutations exist in the resected tumor it does allow you to create very very sensitive tests for that patient and that's what's being done commercially are these bespoke assays based on what comes out in the surgical specimen but when you don't know what you're looking for the argument is if you do enough sequencing you'll find them.

Are there companies or is that all done in the lab right now are there companies that are actually taking it's.

Not yet commercialized no but it's there's a real i mean i mentioned this briefly before there's just a real scale up in investment in this area which is incredibly heartening to see i mean i used to complain for so much of my career about the fact that diagnostics just didn't get the same investment that therapeutics got because the return on investment just fundamentally different like you know fundamentally different between the two domains and yet as clinicians we need the diagnostics we can't even think about therapeutics until we basically diagnose that's the irony of.

It right is if people talk about oh we'd really love to lower healthcare costs yeah you need earlier and better diagnostics it's just such a no brainer i think it's wise to be upset about the cost of oncology therapeutics that are adding no value but you spend a tenth of that on the diagnostics you make that problem irrelevant that's right.

And then the durations of therapy that we need to give people to have curative outcomes you solve so many problems.

By virtue you just say we're turning this into a lock and key model from diagnostic to therapeutic keith we're just about out of time so i want to kind of end with a question that you may not be able to answer but it's worth asking anyway i think of you and people i know like you as the most remarkable oncology advocates meaning i know that if one of my patients comes down with cancer i can call you up and say keith i've got this woman it's a very unusual breast cancer it's her two neu positive but erpr negative there's something funky about it going on who do you like who should she be seeing and let's say there's another situation where a traditional therapy is failing and you know you're gonna point me in the direction of where there's a clinical trial that's promising not just a phase one that's like probably got no hope but here's a phase two that really has some hope okay so there should be an entire industry of keith flaherties who are there to be consulted by families who find themselves in this situation because again we come back to how we started this discussion there's nobody listening to us right now or watching us right now who hasn't been touched or will not be touched by cancer and even if it's a cancer that ultimately doesn't kill them which again in about half the cases it won't actually kill you you will need help navigating the system and the disparity in cancer care in this country and probably in most countries is significant and therefore it does matter who you know it does matter which expert points you to the best treatment center because i can't clone keith and a dozen other people that i know that i can pick up the phone and call what does that look like what can somebody do when they get.

That bad news this drives me crazy what you're talking about in terms of access to expert opinion when you need expert opinion and particularly for complex unique outlier cases if you will you don't know as a patient or a family member whether you're dealing with a middle of the road case how would you know so first off we need to pool our insights if you will break down the silos of hospitals and centers and universities and whatever and pull our opinions that's kind of point number one point number two is we need to leverage technology for this purpose people get all excited about artificial intelligence in terms of how it's informing chemistry advances and the like and you know i'm excited about those things too and then other aspects of biology discovery and all that but this is the most obvious use basically right is that essentially you start to build the database essentially of opinions that i and others offer to specific cancer cases based on certain aspects of their diagnosis and the patterns are these are not hard for a machine to figure out i mean a human could.

Figure out it's sort of codifying what you do what you do very easily as the teaching set for the ai.

Exactly and what i'm getting at is within the ninety five percent boundary of typical cases the decision support can really be based on the last hundred cases that i and my other melanoma colleagues have seen that are just like that this and then the edge cases is where we need to apply our specific attention i think there are actually enough of us to handle the edge cases the problem is the way our system works is nobody knows what their complexity of their diagnosis is everybody's seeking the same level of care and sort of decision making without that understanding and we can get way ahead of this and be transparent in explaining like look here's why we're saying you've got a very typical case we have a ton of outcome data we know what therapy is the very best you know the issue of therapeutic access and investigational therapies that are crossing the divide and are showing real responses in real human beings and should be considered as a certain priority maybe not the top priority but a backup option or something that's also not rocket science and you shouldn't have to get on an airplane never go see anybody but even on the zoom screen i mean honestly this is we are so inefficient in terms of how it is that we disseminate information it drives me crazy there are very few entities but are a few working on this problem and kind of see it this way you throw some technology at this problem i think this goes away so.

What is the best thing that one could do now what are the companies that are out there that are trying to do this now that are reputable.

In your mind n of one's been at this for a long time this is still a model that they're i think quite good at but not the accumulating of the database and again figuring out how to focus attention if you will there's a company i know called xcures that's doing exactly this kind of work but it's still at the helping individual patients navigate level right now what.

I'M yeah it's not the full insight.

Machine that's right but it's going to come i mean this is another area that is under invested we'd really like to see this because we otherwise as you know we're kind of blowing the bank on a very efficient system as it stands right now and it's not scalable certainly not globally scalable well keith.

This was fantastic obviously we're going to sit down in four years again and talk about the last four years which will be going forward from here and i have to say i find myself quite optimistic about what i see happening and i think we'll be talking about some big wins in four years again i don't think we're quote unquote curing cancer but i think we're going to get a lot better at detecting it earlier which gets people into a treatment pipeline sooner and i think we're going to continue to see probably incremental ways to harness the immune system that's probably where i see a lot of optimism and again i think that's in combination with other traditional therapies and non traditional therapies such as the metabolic ones you.

Mentioned totally agree the good news is that the technology curve continues to bend upward right and so we talked about sequencing technology as an example there but cell engineering advances ability to take new molecular targets and rapidly cycle that through to new drugs small molecules antibodies the like all of these advances are converging in a way that if we keep talking at four year increments the pace of progress is going to be substantially greater per unit time we've already witnessed that there's no question that four year increments over my career that's been true it's reflected just in approval of drugs by the fda for cancer but now the convergence of diagnostics and therapeutics that's what's finally coming into view that piece has really i would say been largely missing but if you link up all that we talked about today i think that's the take home message really is it's the crossing of those wires that's what's really going to massively get us towards the path of having many much much higher percentage of patients who are ten year survivors to use that benchmark.

Again well keith thanks again it's been great speaking with you and i will speak a lot more in the next four years but i look forward to hosting you again back in four years and having the next increment of time.

Discussion absolutely really enjoyed it be well.

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