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

Episode Date: August 21, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Keith Flaherty is the director of clinical research at the Massachusetts General Hospital Cancer Center and a previous guest on The Drive. In this episode, Keith first delves into the statistics on cancer's prevalence as we age, underscoring the significance of finding effective treatments and early detection methodologies. He touches on the history of cancer therapeutics and illuminates the notable enhancements in cancer therapy within the last decade that are setting the stage for a promising future. He goes into detail on the potential of immunotherapy and therapies that can combat cancer’s evasive tactics while explaining some of the existing challenges around specificity, cost, and scalability. Additionally, Keith highlights the significant leap in early detection methodologies, namely liquid biopsies, which have the potential not only to determine if a cancer is present in an early stage, but also identify the possible tissue of origin. We discuss: Keith’s interest and expertise in cancer [3:15]; Cancer deaths by decade of life, and how cancer compares to other top causes of death [7:00]; The relationship between hormones and cancer [12:00]; The link between obesity and cancer [18:45]; Current state of treatments for metastatic cancer and reasons for the lack of progress over the decades [22:30]; The interplay between the immune system and cancer cells [32:00]; Different ways cancer can suppress the immune response, and how immunotherapy can combat cancer’s evasive tactics [39:30]; Elimination of a substantial portion of cancers through immune cell engineering faces challenges of specificity, cost, and scalability [52:15]; Why TIL therapy isn’t always effective, and the necessity for multimodal therapy to address various aspects of the cancer microenvironment [1:01:00]; Potential developments in cancer therapy over the next five years: T-cell activation, metabolic interventions, targeting tumor microenvironments, and more [1:06:30]; The challenge of treating metastatic cancer underscores the importance of early detection to improve survivability [1:19:15]; Liquid biopsies for early detection of cancer and determining the possible tissue of origin [1:24:45]; Commercially available cancer screening tests [1:33:45]; How to address the disparity in cancer care, and the exciting pace of progress for cancer detection and treatment [1:40:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. 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 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 the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. My returning guest this week is Dr. Keith Flarity. Keith was a previous guest on episode number 62 of the drive way back in July of 2019. 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 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 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 10 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 yearyear 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 Dr. 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'm excited to discuss with you that we haven't talked about, and I suspect that will make up the line'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. You know, 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, that's, I think that's probably where four years ago that some of the things that had played out would have played out, but on the diagnostic side, that's I think that's probably where four years ago. I was I didn't quite have the crystal ball vision as to how things would develop there. So and of course those two areas are like tightly related in oncology. So decided 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, my medical oncologist, I've been in the field now for 23 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 a Matt Nibbureglyvek was first in patients 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 therapy. So I've been doing that for 23 years,

like anybody in the academic medical world in oncology, I had focused on specific cancer types, so melanoma and kidney cancer, and both of those I chose because of 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 therapy 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 of understand mechanisms of action, mechanisms of resistance. In other words, wind 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 10 years, I've co-founded now a handful, a little bit more than a handful, biotech companies with Locksox on College of Being the First, 10 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 prime time to move forward. And then again, trying to translate my 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 pulled 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 10-year increments, just from 25 to 34, 35 to 44, et cetera, all the way up to north of 85. 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 25 to 34, it's 6%, 35 to 44.

It's 13%. Think about that for a minute. That is a staggering number for people so young. But the time you get up to 45 to 54, it's 23%. 55 to 64, 30%, 65 to 74, 31%. 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 25 to 34, 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 could 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 cancer and very likely died as a result of it. No, that's a good reminder. One interesting thing, maybe just to break that data down a little bit. People think of pediatric cancers. Of course, those are like, if your life has ever been touched by a kid with cancer, there's almost nothing more jarring, almost seemingly unjust, if you will, about a child

being diagnosed with cancer. For children, cancer is 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 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 20s, 30s, 40s. 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, it causes those cancers and some people, you know, so vulnerable to them. And then, you know, carcinogen induced cancers, well, melanoma, of course, 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's 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 relatively not top of mind for people, but even when you get to bladder cancer, which you think,

how does smoking cause bladder cancer? And it's not the sole cause, but it's certainly a big contributor. These sort of smoking related cancers, they take exposure, obviously, and a bit of time to accumulate their population impact, ultimately. And just one of the things 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, and a little bit of smoking influence on breast cancer risk. But there it's, you know, 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, you know, cardiovascular disease, and neurogeneral 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 50% 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, it'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 20s and their 30s and even in their 40s, cancer is never to be found. I can't say shows up only when those hormones are long gone, 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 and 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 of thinking. Yeah, no, that's a great point. And actually, it's kind of very tempting to insert here, sort of deep cancer biology principle. If you look at other cancers, then breast and prostate, the cancer types where we've really gone the deepest in our understanding of what causes them to become cancers 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 nitis, if you will, the hot spot 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, 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 logins, but still using the receptors and their downstream consequences to drive those cans. 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 got it's probably been 15 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 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 initiation of 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. I use language like they figured out. I think you might remember 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. 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 that a so-called triple negative breast cancer, so lacking hormone receptors and lacking HER2,

which is a well-established surface target, a growth factor receptor on normal cells and on cancer cells, including breast cancer cells, for breast cancers that have figured out how to become a breast cancer. But 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, 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 got drugs. We need more targets. Exactly. 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 the surface growth factor receptors. Those drugs, we've had them for a long time, but also 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 it might have used this term four years ago. We have this scenario in cancer where there's kind of distribution of haves and have-nots. And what I mean by that is we have patients

who's prognosis to start with is better, and whose therapy advances are really accelerating, and like making certain cancers, and hormone receptor positive breast cancers, quite a good example of this, where additional drugs now have been successfully developed at its combination since we spoke four years ago, even now FDA approves in 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're 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. We're long 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 what I refer to as classical chemotherapy drugs of kind of the pre-2000 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 to the spectrum. Yeah, a couple of 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 IGF1, not to mention the inflammation that is part and parcel with that, which I assume is in some way impairing the immune system

in 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. Cholorectal 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 25, 26, maybe 27 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 ultra-vout radiations, 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 a 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 where we started

with the hormone receptor-driven cancers, 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 that then regulate how the mitochondria act as the power stations, if you will, inside of cells, to the so-called PI3 kinase pathway, well described as being a driver and 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 there's something about that pushing, that driving. It's like chronic inflammation,

as you've cited, which itself, by the way, forces a direct causal factor for certain cancers. 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 and so. So I remember in in January of 2000, I'm in my last year of medical school and I trek across the country from California to Bethesda to go and spend four months as a medical student rotating on the immunotherapy service with Steve I was there from January until April of that year. I mean, literally one of the most joyful examples of pure bliss, and I was there for the first time in my life. I was there for the first time in my life.

I was there for the first time in my life. I was there for the first time in my life. I was there for the first time in my life. I was there for the first time in my life. I was there for the until April of that year. I mean, literally one of the most joyful examples of pure bliss. I had, I've told the story before, but I, I think I told the story when I had him on the podcast, you know, 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 wanna be out of there, and I wanted 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 30 years, we have basically made no progress in the long-term management of metastatic

epithetial cancers, translating that into English. If you had a solid organ tumor that had spread to a distant site in 1970, the chance that you were going to be alive in 10 years was the same in the year 2000, and that was basically zero. Now, there were a couple of small exceptions, and they happened to be the cancers that you and he are both interested in. There were about 10 to 15 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 90% of patients who had metastatic renal cell carcinobin melanoma. How are we doing today? 23 years later, do you have a sense of how much bigger that number is? So if we went from 0% 10-year survival in 1970, and I'm using 10-year to really try to get out some of the median survival extension stuff. But if we were 0% survival for solid organ tumor in 1970, call it 1% in the year 2000 on the back of the few cases of RCC and melanoma. What are we at today? I think 15% is a conservative number. Some would make a case for 20%.

I think the problem is there that we need a little bit more time, some of the newest therapies in our own... We don't have the 10 years. Yeah, we don't have the 10 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 20%. 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. You know, 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. And so 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 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 side 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, oh, a little 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. We've won two and three years, this 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, you know, the features of their primary tumor as well as lymph node involvement, a substantial fraction of those patients. Let's go with 30, 50 percent kind of a typical range. Over those few to several years of follow up, we'll 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. 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 medicine disease. That's the term I wanted to kind of insert in this conversation is microscopic medicine disease. I will 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 15 moving towards 20% range, 10% 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 20% number. Half of that advance has come from one therapeutic modality, PD1 and a body-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 0.2% 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 10-year numbers, it's an astoundingly long survival by historical standards, because metastatic cancer will prove fatal in nearly everybody untreated within that timeframe, even the most quote-unquote indolent cancers. Yeah, so let's just kind of go back and restate the important part of that. So basically 1970 to your 2000 zero progress has been made 2000

until now we've probably been able to make a small dent in that. Half of that dent has been on the back of K Truda. How many drugs are in the other half of that? So we mentioned Gleeve acumenodigo. That was probably the first. There've been 52 FDA approvals, but that's against 19 unique mechanisms, right? So there's a lot of meat toism. Ministers true in all therapeutics, not just oncology.

I tend to go down to that number. 19 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 it's immediate downstream component and the immediate downstream component yet again, that would then count as three on that list of 19,

but really they're very overlapping. So if I were to really boil it down, we're kind of in the 10 range in terms of, you know, truly unique molecular targets. And Katrina does have company, so this target of Contruda, just for those who are trying to keep up with the jargon, as they do, they're Google searching on any of these topics. The target of Contruda is P, capital P, capital D, hyphen 1.

That's a surface receptor on certain immune cells, particularly on these CD8 positive T lymphocytes that can kill tumors directly, but there are other immune cells that express PD1. And that's a break on those immune cells. So the antibodies that block that break are the so-called PD1 antibodies. There are five of them that are FDA-approved. And Catruta or Pemperlyzumab 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 toism before, there's lots of me toism in that space. And then is anti-CTLA for still being used or is that mostly just being used in melanoma? What's the prevalence of its susceptibility versus that of PD1?

For cancer types now and most would argue a fifth have evidence that adding CTLA for to PD1 as another block. So that's another break on the immune cells, on those same T-cells. It was actually discovered before PD1 as a target and the therapy was advanced against it a little earlier than PD1. But a much smaller percentage of cancer patients get a benefit from that drug. There's some evidence that they actually can act kind of independently, sort of exert its

own benefit. But I'm describing that 10% number, by the way, there's some real that they actually can act kind of independently sort of exert its own benefit. But I'm describing that 10% number, by the way, there's some real math behind that. It's not totally like just a good stalled number of patients who get long-term benefit from PD1. If you add in CTL-4, you're in the 1% range in terms of the addressable population for CTL-4 antibody therapy

who derived then 10-year type benefits. So PD1 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 till, 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 got a buckle, your

seat belt 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 could only put 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. What do we learn over the decades on that topic? There are a variety of differences. I'm gonna 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, by all mature cells in the body come from 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 cancers, 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. So 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, testus, 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 cell, but we see that. We see evidence that the immune system reacts to those and that there are cell therapies, as you were alluded 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 the meaning on the cell surface in the context of these molecules we refer to as major histocombatability receptors as they're kind of alluded to. But the idea is that they're trying to show the wares, 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,

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, stop presenting antigens at all. The antigens, the new word I meant to introduce that.

Antigens 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, we're trying to hide itself, if you will, by not expressing these receptors to present antigens. Then there's actually a branch of immune system that's basically natural killer cells, as they're called, the very primordial immune cells, they're 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 anthropology 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, is 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

begin to increase the toolbox, if you will, of handles that the immune system can latch onto. So if you think about it that way, the 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 ordn northern amount of evidence in support of this idea that if at least keeping them dead, you proto-cancer is down, if not outrided, and name them. Is that 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, we might say we again using the anthropomorphic inside of a cell 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 cancer, something's gone wrong. The system didn't work to detect, you know, 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 it, 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. Imagine having a flu forever, like just dumping cytokines

or immune system hormones into the bloodstream, cranking up body temperature, consuming a ton of metabolic resources, infighting infection, and feeling bad as a consequence when you have the flu. You can't do that indefinitely. You've got to stop immune responses. And so we have mechanisms to do that. It turns out very elaborate, said a mechanism 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-1, PD-L-1 story. So PD-1, we've talked about. That's the target of Catruda. But what cancers do, so nasty little trick, is they figured out how to, not all cancers, but the ones that are most responsive to Catruda, they have figured out how to express on their surface. The foot, that presses on the break. So that's called PDL1, so program death, hyphen, L1, ligand1, which basically reaches

across to PD1 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, what figures out how to express that protein. And so then blocking, you know, the interaction of the foot with the brake, that's the magic.

There it is. Now that's just one mechanism, but as the break, 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 ureka moment with the success of PD-1 drugs, but with 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. Like, 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 80% of epithelial tumors had novel neoantigents. 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 20 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 80% of epithelial cancers have novel neoantogens, a totally staggering feature that had people understood that 20 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, the kind of biology behind this. So mutations accumulate in a cell that's going to become cancer. Fair number. I mean, we're talking, you know, nevertheless, the 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 know, you inherit kind of half of your set for 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 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 what's called the 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, 80% of, so when you do epithelial cancers just remind people, like breast, colon, prostate, lung. It's not leukemia and lymphoma. And brain tumors, right? Yeah, not leukemia and lymphoma are brain tumors. And melanomas, we mentioned before, this actually come from melanocytes, which are

neural crest, origen, 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 fetal 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, like to meet the definition of energy, you have to find in a human being that the mesysm can actually see it in the context of it being presented on these MHC complexes. And it turns out that it's kind of a lock-in key concept, essentially. It has to structurally work out that the protein fragment is being presented, you know, in the T-cell receptor, docking in, and seeing that version, but not the unmuted version,

where that difference is enough to basically tell the T-cell, go, kill. Yeah, so these exist. Like 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 PD1 and CTL-4 we're 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, such 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 neo-enegins. 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-1 has been efficacious. Like, we didn't know this when PD-1 and C-2 were antibodies were first being developed. It was this interplay that we could then just add one drug that blocks this foot on the break, as I mentioned before, and bam, you unleash these preexisting 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's even, I'm sure, talked about with you,

is well, we can actually engineer immune cells to attack these things. Basically, potentially overwhelm other ways of the immune system that cancer should protect themselves from the immune system, which is what cell therapy of various kinds can do. So, you know, 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 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 incidents 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 1960s. He's a resident at the Brigham. A patient comes in who 10 years earlier had been sent home to die with metastatic gastric cancer throughout his liver. They took his stomach out to peliate him and he should have been gone in three months.

He shows up 10 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 20 years, yeah, almost 20 years, right, was figuring out that if you just dump enough interleukin too, which is candy to tea 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. If we just dump enough interleukin too 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 run, spontaneous mutation, spontaneous response. You don't even have enough that if I just gave you IL2, but if I give you a more sophisticated help, turning down the suppressor, now it's gonna work. But to really unlock this, to basically say, we could make 80% 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 80% 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? You know, just to connect the dots from early versions of South therapy to where we are now, you know, Steve Rosenberg's work was so called adoptive T-Salt 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, whichastatic 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 in any case, immune cells don't traffic at high numbers through all cancers, but certain, quote unquote, immunogenic cancers, yes, they do. Melonoma, again, being near the top of the chart

there. What Steve was doing through the 90s, 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. To a number that when he infuse them back, could then, you know, systemically, could then traffic through the body and destroy people's cancers not 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 FD 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. Netwood's been learned along the way is exactly what we've already summarized, which is this idea of antigen specificity that you can find this kind of, what is it that the immune system is seeing? These infiltrating immune cells and 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 care of 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 80% of patients. We can identify a mutated antigen that will only be in the cancer cells and introduce into their immune cells as surface recognizer, if you will, I'm just being vague about the term, not to 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. But 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 CD19. 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 CD19. And when a subset of B cells go on to become lymphoma that is otherwise unresponsive to other treatments, low and behold, you could wipe out, you could basically send in someone that's going to target every CD19. 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 40 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 12 month prognosis. But because he had linch, and this was 2012, maybe, maybe 2013, it was just around the time that a paper had come out in the England Journal of Medicine that had mentioned, hey, if you have mismatched mutation genes, you might be a candidate for this new anti-PD1 and this story is a happy ending in that sure enough, he got the anti-PD1 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-19 approach

is gonna 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, you know, what is truly specific for ventures?

These mutations. It's a big hill to climb that I haven't. We haven was honing in on, you know, what is truly specific for events, cells, these mutations. It's a big hill to climb that I haven't, 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 in 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. You can direct chemo, even an antibody that's on the back end of it has chemotherapy drugs that get 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 clinical data and now some improved 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, you can, you're gonna 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 like feeling blindly and just trying a bunch of things, because of the power of the killing potential of these immune cells, there's every constitu real conundrum. Like feeling blindly and just trying a bunch of things, because of the power of the killing potential of these immune cells, 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 is more CD-19 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 the point of being able to create by functional recognizing elements. So these surface recognizing receptors, where basically both of the targets have to be present, till like an end switch, as it's called, like the Boolean end or instead of just creating a cell that goes after CD19, you create a cell that goes after CD19, you create a cell that goes after CD19 and CD20. And you only ever kill a cell that's got both.

Actually, that's not a perfect example because CD19 and CD20 are almost always co-expressed on B cells. But in 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 manufacture. We have a lot has to happen for that to be remotely feasible, economically manageable. Let's go back to Till for a moment. You mentioned that they're on the cusp of receiving an FDA approval for the treatment of metastatic melanoma. 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 TIL. 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're have to actually undergo lung surgery and take out a wedge or a 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, I've been so long since I've been at it, I think they want to get to at least 10 to the 9, is that the word or magnitude? Okay.

You expand this to about 10 to the 9 cells and they're re-infused, usually within or looking, 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 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 PDL-1 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,

it's 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 media 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 PD1 antibodies. We've demonstrated in melanoma and 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 they're contending with. But then you've also got that recruitment of suppressive immune cells that I alluded to before, which especially very antigenic cancers, very commonly do that, need to do that. And you can't overwhelm them just by introducing more CD 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 old at all. And then there are trafficking issues, basically features of cancer micro environments. Some of them related to oxygen tension, some of them related to nutrient availability, that make very challenging for immune cells to persist, you know, 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 a very low oxygen gradients.

People didn't really understand like the why of that. But you're describing of course stems in part from the warburg effect, which has always been people who 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? Well, 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. You know, my argument is when I talk about multi-modality 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 positive 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, like 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, I mean, a much more completely. It's just, in my strongly held view, it's not going to be for therapeutic maneuvers all in column A or for 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 till. 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 this 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 at least referenced one study that had taken patients, I think with lung cancer, none of them had any PD-1 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.

You know, 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 time frame short, which is five years, what are we gonna 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, CDE-positive T cells, most notably, and we know what those gas pedals and brakes are on those cells. And we have tried drugging those, typically on top of PD1 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 for whom 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 were, and remain, hypotheses along those lines that were never really tested. So anyway, just trying to hyperactivate these 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, 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 warbird phenomenon that you alluded to, and the regulators of that switch, those have become elucidated on 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, right?

Because every cell in the body needs to be able to regulate its metabolism in a, you know, condition dependent way. That's true. But cancers really do 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 to 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 gonna interfere with any ends time 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, you know, 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 100% with you. Basically, you can't poison 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 is called, like there's many different mitochondria, or many mitochondria per cell, different cell types, you know, need different numbers of them, based on their metabolic demands. So cancer cells will actually regulate, you know, the amount of mitochondria they have through these outside of mitochondria programs, if you will, transcription

vectors, in many cases 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 like the top differentiator, if you will, expressing cancers and not, and others. Now, it's 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 gonna bear out, but these are the types of insights we just didn't have five and certainly 10 years ago, that there might be ways to actually laser in

on the regulators and metabolism that cancers are most potentially vulnerable to. And I'm not suggesting these are gonna be standalone approaches, as I said before. It's rather than a potent, yeah, they're gonna potentiate these other therapies. And we 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 service 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 persistent cell population in both therapy types.

And so the idea that you would then potentially, simply what we've already got with this class of therapies go from 20% of cancer patients having long-term survival to 40% of them, 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, 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 drug exposure all the time to be able to get away with it, which is a common theme

in terms of thinking about for 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 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 out once, we have repair mechanisms, but if they don't do their job, then a cell basically has a program by which it commits suicide, so-called program 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 that accumulate because of the defective machinery is just off the charts, like ultraviolet radiation associated skin cancers, also off the charts. In 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, you know, to what they can handle. So how about combining that concept with what we were talking about before, of immune system recognition, immutated proteins, and just say, hey, okay, you want mutations,

and it can go 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 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 10X the number of mutations you have, both to increase immune recognition and possibly also just simply push it. Dr. H. Dr. David T. Dr. David T.

Dr. David T. Dr. David T. Dr. David T. Dr. Dr. Dr. Dr. Dr. Dr. Dr. Dr. 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. Parpe 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. 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, you know, 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 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 a innate immune function, but there's pretty good experiment 11, and it's that you have to start with something

that's at least shared in 95, 98, maybe even 99% of cancer cells. So this is where the idea of like, you know, using, let's say, radiation to treat like a single site of metastatic cancer and someone who's got 20 sites, we've tried this. It hasn't worked or are very sporadic cases where actually can trigger a much more profound immune response

that's actually systemic, like it 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 10% 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 program cell death, or it now finally rises to the level of detection. But that's not sufficient enough across the entire organism. Yeah, well, I'm clear the rest of the tumors. Then being in a concollege, as 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 incubating, I mean, actually in living being, 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, PD1 and a body-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 that would appear, you potentially can introduce the mutations without having some of the dilataries of X that chemotherapy drugs are well known to cause. Keith, I'm gonna 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 wanna 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 full fox and all that stuff, but there's a regimen of chemotherapy.

You'd put that patient on. How many of those patients are going to be alive in five years? 60, 70% of them? Yeah, that's about right. Again, it depends on the size of the children who are in other features, but that's about right. Yeah, again, it depends on the size of the children, or 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 going to go ahead and cut the colon out, take those lymph nodes out, but on the CT scan, you're going to notice that he's also got metastatic cancer.

So one of them is stage three, one of them is stage four. We're going to give that stage four patient the same chemotherapy. We're going to 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 10 years, it's none. Yeah. Yeah. 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, like why is it that we're actually able to eradicate microscopic residual disease with the same drugs that don't do the job when you have macro disease? Yeah, like I was going to say. In other words, why does it work when

you have hundreds of millions or billions of cells not all clump 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 they'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 99% of cells. And then in that remaining 1%, you might have 10, 20 subclones. We've proven now that certain therapies actually able to pick off the 99%, they leave the 1%, and then somewhere in that 1%

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 period of 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, those growth factor receptors and downstream ones in particular, it's very clear. You can cure trivial fraction of patients with over-at-ministraties, and you can cure a pretty substantial fraction of patients

in the so-called adjuvant setting, so microscopic residuality 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 clinical 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 systems job. It was a concept that was first introduced when we had just these conventional chemotherapy drugs from the 1900s. And now we actually have more and more evidence that are 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. I think it's reasonable to then overlay that on top and say, well, yeah, extending your spontaneous remission starting point from a while ago in discussion, that basically you're allowing this tipping point phenomenon to occur. Yes, you're directly killing cells with these drugs. That's true, but the eradication piece, his ultimate immune system, phenomena. And I think there's kind of a hybrid there too, right, Keith, which is that in the micro-matasticies 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.

That's right. 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 its 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. Yeah, right. 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 can also, hopefully, eradicate cervical cancer by getting everybody vaccinated. That's the BVX, yeah. Exactly. But cervical cancer screening, absent of 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. Coenoscopy and other less invasive means of detecting colon cancer can reduce risk of colon cancer death by about 25 to 30 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 is,

again, particularly inspiring. And despite lots of effort and, let's 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. 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 hyperglangular tissue. The exact opposite is true with the MRI. Similarly with the PSA by itself, virtually meaningless, but PSA density, PSA velocity, now adds much more specificity. Furthermore, you start to add things like a 4K, and if the risk is high enough, you get a 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 10 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 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 4K. 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 poop who's it based on what I still think are impressive numbers the number used 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 seat belt on, you could not drink while driving, and you could mind the speed limit. That's a totally different situation than saying we're're gonna 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 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, maybe 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, you know, from a single 10-millimeter tube of blood, and particularly one collected over time, so kind of a now-agust 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, you know, almost pan cancer tests. But in R&D mode right behind them are 10x, 100x 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 what I just described, the fact that on circling tumor DNA, as it's called, you can actually do more than just sequence for mutations to find that it's circling

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 a 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, 12 months, 18 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, 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 medicine disease versus microscopic disease that remains after surgery, aka adjuvant setting. But now finding cancers at a point where there's many fewer of these cells and where, you know, the defense mechanism is a force field, so 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 there you know what you're looking for. You've taken out the patient's lung cancer. 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. No, no, no. If you solve this problem, you win the game. We've always been stuck in this mode in cancer research and therapy development, kind of start with the worst case scenario, if you will, right? And then... And that's where you have to learn.

That's right. And the same therapies that are somewhat effective in the overt medisatic setting are much more effective in this so-called adjuvant or post-searchable 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 intercepting the cancer. When the immune system is still quite competent, it's 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? And 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 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 are 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 the under-rated 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, you know,

generalists who really develop expertise, contact knowledge, have a network of specialists that they can work with, and 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, like, direct head, head, comparison analyses, like, of how much lower can we go in terms of, you know, amount of tumor DNA in the blood that can be detected with, you know, what are currently R&D methods, but are readily scalable. We're really at 100x better. At that point, you're talking about a finger drop a blood. If you're 100x better than 10 ml, you mean? Okay, that's true.

You could take it in that direction, but we actually, you would say no, stay with 10 or 20 ML and 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, at least until we do more studies.

What's differentiating these companies? So if you just look at Delphi and Grail. 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've got to 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 sequence in 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 circumvent your 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 circling to 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 circling 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. That methylation aspect that I talked about before, that's the other feature that has

been a differentiator in terms of the first marketed products in this class, even across these three companies, but there are 10 more companies coming right behind. Basically, the first one is not valuable 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, the cost of sequencing continues to nose dive.

I believe it or not. Still going down lower and lower costs 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 10,000 most common, the 100,000 most common cancer mutations that we actually can... Yeah, I mean, I guess if you had K-RAS and you had... P53. Yeah, P53 and yeah, it'd be rare.

P53 is mutated in 50% of all cancers. The problem is... There's hundreds of different diseases. Exactly. It's a big gene. But still, people used to object to that concept based just on a sequencing 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-sortical 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. That's what's being done. Echmercially, 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 there's a real, I mean, I mentioned this briefly before. There's just a real scale up an 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 therapeutic's got because the return on investment just

fundamentally different, like 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 it 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 cured of outcome, you solve so many problems by virtue of that. 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 new positive, but ERPR negative. There's something funky about it going on. Who do you like?

Who should she be seeing? Let's say there's another situation where a traditional therapy is failing, and 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 Flarities 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 at what you're talking about in terms of access to expert opinion when you need expert opinion when you need expert opinion, and particularly for complex unique outlier cases, if you will. And 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 pool our, you know, kind of 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. I'm excited about those things too

and in other aspects of biology discovery and all that. But this is the most obvious use, basically. Is that you 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, human could figure out. It's sort of codifying what you do, what you do very easily as the teaching says for the AI.

Exactly. And what I'm getting at is within the 95% boundary of typical cases, the decision support can really be based on the last 100 cases that I and my other melanoma colleagues have seen that are just like 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, like the way our system works is like 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 and explaining, like, look, you know, 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 and 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, we are so inefficient in terms of how it is that we disseminate information. It drives me crazy. There are very few entities, but our few, we're working on this problem and kind of see it this way. You throw some technology, 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? And of ones 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 gonna come. I mean, this is another area that I'm undered. 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 Metabolical ones you mentioned. Totally agree. The good news is that the technology curve continues to bend upward, right? And so we talked about sequencing technologies in example there, but cell engineering advances, ability to take new molecular targets and rapidly cycle that through to

new drugs, small molecules, antibodies, 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 for your 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 10-year

survivors to use that benchmark again. Okay, 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. Thank you for listening to this week's episode of The Drive. It's extremely 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

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