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

25:09Yeah, 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, 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.

25:42This is not true for all cancers, but certainly true for the common epithelial cancers your focus 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. The sort of the analogy, right, is like when people leave a city in an airport and go to another airport that's in another city, we don't call it spread until they leave the airport and go to the city proper. Even though they've clearly demonstrated the capacity to go from their house to the airport, hop on an airplane, go to another airport, and once they step foot out of customs and collect their bags, well now we can say they've really spread.

26:22The 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 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.

26:52How do we know that some of those people actually have metastatic disease? At that time, well by following them, five and ten years will not even that long. We've won two and three years. This is in fact enough for most of the aggressive cancers. You do the surgery, you clean the slate, you do scans, you know, of various kinds, you see nothing. And basically a substantial fraction of those patients, depending on the cancer type and depending on how much the features of their primary tumor as well as lymph node involvement a substantial fraction of those patients. Let's go with 30 -50 % kind of a typical range over those few to several years of follow up will manifest metaside disease.

27:25Well, 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 menacea disease.

27:58That's the term I wanted to kind of insert in this conversation. Microscopic menacea disease. We'll come back to this, but let me just pick up on this theme again for evident overt metacetic disease when you can see it on scans or clinically witnessed 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.

28:32A 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, it within that timeframe, even the most quote unquote, indolent cancers.

29:19Yeah, 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 Trudeau. How many drugs are in the other half of that? So we mentioned Gleeve, I mean, a minute ago that was probably the first. There have 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.

29:55And 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, truly unique molecular targets. And Contruda does have company, so this target of Contruda, just for those who are trying to keep up with the jargon as they do their Google searching on any of these topics, the target of Contruda is capital D, hyphen one.

30:37That'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 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?

31:14What'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 percent 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 math behind that.

31:48It'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 derive then 10 -year type benefits. So PD -1 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.

32:23I 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.

32:59So 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 I 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 have put only that except for the fact that we unfortunately hold on to self -recognizing immune cells and those can cause autoimmune disease, which is not the topic of our conversation today.

33:39But 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 going to start here because it's going to give us a little bit of chronology in a way. We began to understand some time ago that a common feature of cancer cells is that they behave like their sort of progenitors or precursors, like in development. All mature cells in the body come from a 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.

34:17This is just a consequence of the genetic alteration, sort of the combination lock, as I often and referred 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.

34:49So just think of that as kind of this developmental sort of biology. Turns out there are also interestingly some what we refer to as linear genogens. So like surface markers that tag a certain, you know, 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 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.

35:30So 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 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.

36:02Because we think that because of that, that virally infected cells have an infection inside, We think this is how this machinery was ever, you know, how it ever evolved in the first place. And so kind of showing the inner contents, if you will, is 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. Antigen means a difference, like a protein fragment that's being presented and seen as different.

36:34We call that an antigen, and it can come in these different categories that I'm talking about. So basically 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 that are called the very primordial immune cells that are supposed to just swoop in and kill those cells. And we have evidence that that does occur. So let's just pause here Keith to make sure people are following the 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.

37:09So 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.

37:55So failing to play the game results in a loss of home. That's right. Well said. And 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.

38:28So 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, 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.

39:01This immune surveillance concept is an ordinary amount of evidence in support of this idea that if at least keeping them dead, you proto -cancer down, if not outright, I'll 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.

39:36The 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 Let's 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 Like you can't just elaborate immune response, you know indefinitely I mean imagine having a flu forever like just dumping cytokines or music 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.

40:24You can't do that indefinitely. You've got to stop immune responses. So we have mechanisms to do that. Turns out very elaborate set of mechanisms to do that. And cancers have just ever so craftily figured out how to basically reach into the genetic code, the blueprint, and co -op mechanisms that will basically We impede immune system recognition and response. That's the PD1, PDL1 story. So PD1 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 brake.

41:05Okay? So that's called PDL1, so program death, hyphen, L1, ligand1, which basically reaches across to PD1 on T cells and tells them shutdown. 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. 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, it figures out how to express that protein. And so So then blocking the interaction of the foot with the brake, that's the magic.

41:44There 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. 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 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.

42:20So it's like almost like assembling a force field by virtue of inviting in these non -cancerous cells. This is like the cancer cells recruiting in these suppressive immune cells. So this is some of what we're up against. I mean I just want to make it clear how kind of complicated it is. Yes, we're super grateful to have had this kind of eureka moment with the success of PD -1 drugs. But cancers have co -opted multiple mechanisms by which they defend themselves. In terms of trying to close the gap then and use this immunotherapy concept, much more broadly in cancer, is going to require us to develop the understanding of, okay, well, which tricks are being pulled and how to be able to really target those very specifically.

43:00We can't disable people's immune systems. That's not okay. And so we do need a fair amount of precision and figuring out kind of the sweet spot, if you will, in terms of what mechanisms cancers are using for this purpose. All the things that Steve talked about when I interviewed him last year, the one that I was most blown away by, which spoke to my time away from the trenches, time away from what you're doing day to day, was that roughly 80 % of epithelial tumors had novel Neoantogens. 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.

43:51Just 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, meaning 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 gonna sell yourself to us as an interesting person that we should let into our program, and you're talking about that crap.

44:26Like, it literally means nothing, okay? It works on melanoma, who cares? Okay. Why is the fact that 80 % of epithelial cancers have novel Neo -Anthagin's, 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. We're talking, nevertheless, the dozens in the quote unquote, most genetically simple cancers, but you're typically into the hundreds and thousands.

45:03And basically, not all of those have a consequence to the point about these antigens. So some of them are in parts of the gene on the donate code 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 wears. We show selected representation of them. In other words, these MHC molecules, you inherit kind of half of your set for your mother and half of your set for your father.

45:38They have a ability to grab just certain protein fragments and present them. When I say grab, they're like actually loaded onto those by a cellular machinery that's quite elegant. And so the point is we have this repertoire of showing the inner contents. And so only certain mutated genes that translate into 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 use epithelial cancers, just remind people like breast, colon, prostate, lung.

46:11It's not leukemia and lymphoma. And brain tumors. Right, yeah, not leukemia lymphoma or brain tumors. And melanomas, we mentioned before, this actually come from melanocytes, which are neural crest origin, which are actually share common features with brain tumors. But basically, just to be complete, it's all the rest of cancer. What's astounding is that basically, you can find evidence that these mutated proteins are being presented in the vast majority of these common cancers. And here's the point. We are born with, well, born and during early fetal development after birth. So 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.

46:56The 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 immune system 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 un -mutated 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.

47:28You know, of course, we were sequencing cancer genomes a ton at the time. And we figured out as PD1 and C2 -04, 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.

48:02That'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 PD1 has been efficacious. Like we didn't know this when PD1 and C2L have where antibodies were first being developed. That it was this interplay that we could then just add one drug that and blocks this foot on the brake, as I mentioned before, and bam, you unleash these pre -existing T cells against these presented antigens. But that does explain a ton of the benefit that we've covered already with this so -called immune checkpoint antibody approach.

48:37So 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 that 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.

49:08Let 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.

49:44They 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?

50:21Where, 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. You know, they took his stomach out to paley at 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.

50:58This 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 inner luke -in -2, which is candy to T cells, you're going to pick up the next threshold, which is in melanoma, in renal cell. At the time, we didn't know why, but as you point out, they just have so many freaking mutations that you're bound to just stoichiometrically come up with an antigen that's going to be your lottery ticket.

51:39If we just dump enough inner luke -in -2 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 runs, 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 going to 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.

52:14If 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 -South therapy. Let's not focus on that jargon in terms so much. but basically doing a surgery to remove a single site of cancer, metastatic cancer, removing the immune cells that had found their way into that cancer, which turns out actually some of them are seeing antigens they're specific for.

52:50Others are just trafficking through and they're kind of bystanders as it turns out. But in any case, immune cells don't traffic and hide numbers through all cancers, but certain quote unquote immunogenic cancers, yes, they do. No one knows, 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. Yeah. 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.

53:24Not 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 hefty 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, you know, this kind of, what is it that the immune system is seeing?

53:53These 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 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 center, care these days, but you do it a little bit deeper, a little bit more in a systematic, thorough way.

54:34Basically, 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, a surface recognizer, if you will, I'm just being vague about the term, not get lost in too much jargon all at once, and then basically just dial up that number of cells in the laboratory and then infuse them back like a blood infusion, which is how cell therapy is given. And that's the approach that translates, you know, connects the dots that we've covered. We are not doing that today to be very clear. The cell therapy advances beyond just simply expanding the tumor infiltrating immune cells or lymphocytes beyond that approach.

55:13The 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. 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.

55:49So 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 CD -19. You'll get rid of the bad guys, you'll get rid of some good guys, unbalance its worth it for sure.

56:27But 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.

57:02Again, a great surprise when you're 40 to develop a stage 3 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 six to 12 month prognosis. But because he had lynched, and this was 2012 maybe 2013, it was just around the time that a paper had come out in the New England Journal of Medicine that had mentioned, hey, if you have mismatched mutation genes, you might be a candidate for this new anti -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.

58:02Do we not have enough novel proteins on breast cells or prostate cells that the CD -19 approach is going to work anywhere else? Is that a one -hit wonder? Well, I wouldn't say that, but it's true that we're, you know, these T cells are so powerful you need to find handles again on the surface that are truly specific for cancer cells. So I was honing in on, you know, what is truly specific events? Those 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?

58:41It's trying to identify those surface markers, proteins that are truly specific to cancer, and that's what we've been struggling with because there are other therapeutic modalities that don't require quite as much specificity, like you can direct chemo even, you know, an antibody that's on the back end of it has chemotherapy drugs that get and sort of ingested by the cancer cell and have a more localized effect. Radionuclide, so like really powerful radiation emitters on the back end of such molecules. Also, and it's clear, you know, clinical data and now some approved drugs even that are what I'm describing, that there's like a spectrum of selective expression that is not needed there, but for cell therapy, you need it.

59:19Otherwise, you can, you're going to obliterate every single cell in the body. And here's the problem. Cancer's come from us. When they're reading the blueprint, if you will, and translating certain genes into RNA and 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 constituent in the field has no appetite for that. This has been where the field has been anguishing most in terms of trying to understand if there's more CD19 like opportunities, but on common epithelial cells, where we can't destroy the normal version.

1:00:02We need to get to this greater specificity. Let me just insert one final thought here, which is that the cell engineering field has certainly advanced to the point of being able to create by functional recognizing elements. So these surface recognizing receptors where basically both of the targets have to be present. So like an an -switch, as it's called, like the Boolean and or, instead of just creating a cell that goes after CD19, you create a cell that goes after CD19 and CD20. And you'll 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.

1:00:34But 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.

1:01:08Let'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. So again, just to bring people back to what that means, that means a patient with metastatic melanoma who presumably has progressed through all other non -cell therapies and still has harvestable tumor. This is a very important feature of 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 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.

1:02:05It sounds great in theory why doesn't it work every single time you've clearly identified lymphocytes that know how to go there and presumably that's half the battle, why doesn't this work every single time? Again, it goes back to defense mechanisms to a degree. I mean, it's, I talked about that kind of layering of the onion metaphor before, or layers of force fields. It is the case that there's actually direct mechanisms that can impede killing at the tumor cell level. And I talked about like 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 took a viral infected cell or in this case a cancer cell.

1:02:51And 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.

1:03:24So 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 hold at all. And then there are trafficking issues, basically features of cancer microenvironments, some of them related to oxygen tension, some of them related to nutrient availability, that make very challenging for immune cells to persist, multiply and do their killing work.

1:04:12And 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 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.

1:04:44And 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.

1:05:19You 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 fibroplast, 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.

1:05:51I mean, it's just the Star Wars analogy, right? You've got to take out the moon that generates the force field around the Death Star before you send in your fighters to actually try to destroy it. And so to me, we're on the verge of understanding kind of the hierarchy of this biology and how to think about both diagnosing and then treating at this level, but the toolbox has to elaborate much more completely. It's just in my strongly held view, it's not going to be 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.

1:06:32Let's dig a little deeper into that in terms of what the next five years might hold for us. right? So if we're sitting down again in five years to talk about the success of the previous five years, what's likely happened? How much further have we gone in immunotherapy? Just in straight -up, activating T cells, either through adoptive cell therapy via genetic engineering to take peripheral blood lymphocytes and turn them into or engineer them into TIL. Let's put that as a category of therapy. Let's talk about other ways to identify checkpoints or checkpoint inhibitors and or combat the tumor suppressor cells.

1:07:13So 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 PD1 activity, and then a course of platinum -based chemotherapy, all of a sudden rendered a subset of them to now be susceptible to it.

1:07:55In 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 going to need to do to double the response rate? The durable response rate. Within a five -year horizon, I think let's look backwards briefly. Over the past eight years, we have exhaustively tried to find other gas pedals and brakes on immune cells, CD positive T cells, most notably, and we know what those gas pedals and brakes are on those cells.

1:08:37We 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, immune system doesn't get so hyperactivated, like that's not the problem, but it just hasn't moved the needle. Now, I will caveat that by saying that those approaches have been used without any notion of trying to, like, zero in on individual patients and sets of patients for whom, you know, that 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, there were, and remain hypotheses along those lines that, you know, were never really tested.

1:09:24So anyway, just trying to hyperactivate these cells with drugs, I would say we've kind of played that out. 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.

1:09:53The 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 been 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.

1:10:31That'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 -op. 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.

1:11:05People used to hypothesize that mitochondria were defective, that's why they were doing it. No evidence that that's the case. So let's just play out what you're saying. You could take something really draconian and say, okay, there's an end, so we're not going to interfere with any enzyme that turns glucose into pyruvate. That would be a bad idea, because you have to do that if you're healthy. So where else could you target where you disproportionately hurt a cancer cell without hurting a non -cancer cell that's undergoing glycolysis? Our group just published a paper on this topic, like just five months ago, looking quite broadly to understand these metabolic regulators and which ones cancers seem to selectively use.

1:11:41And interestingly, this analysis was focused on immune cell recognition versus lack of recognition, kind of the interplay between these two things. So we already laid out the argument of the idea that cancers, it seems, in part adopt this inefficient metabolic strategy because it allows them to kind of suck in available nutrients and keep them away even from immune cells. So we were trying to unpack that. And basically, when you look in an unbiased way at all of the gene products that are expressed in cancer cells, differently than normal cells, what you see is that it's outside the mitochondria.

1:12:14So 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, many mitochondria per cell, different cell types need different numbers of them based on their metabolic demands. So cancer cells will actually regulate the amount of mitochondria they have through these outside of mitochondria programs, if you will, transcription vectors, in many cases that regulate the program in the genome, this is the nuclear genome, not the mitochondrial genome, that regulate this process.

1:12:49There's some switches there, and one of those switches basically jumped out of this analysis as like the top differentiator, if you will, expressed in 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 kind of bare out, but these are the types of insights we just didn't have five and certainly ten years ago that there might be ways to actually kind of laser in on the regulators and metabolism that cancers are most potentially vulnerable to.

1:13:24And I'm not suggesting these are going to be standalone approaches, as I said before. Rather than a potent, yeah, they're going to 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.

1:13:54That's a very common theme in what we call the persistur cell population in both therapy types. And so the idea that you would then potentiate simply what we've already got with this class of therapies go from 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 like play with where it is that we're ultimately poisoning this process. And we may have to do it which is 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.

1:14:29But 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 all at once. We have repair mechanisms, but if they don't do their job, then the cell basically has a program by which it 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.

1:15:08I 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, immune system recognition, immutated proteins and just say, hey, okay, you want mutations and can go back to my anthropomorphic.

1:15:40Now 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 them towards. Dr. Matthew Tord. So death. Yeah. That concept is behind platinum -based chemotherapy's effectiveness in cancers that are somewhat deficient in repairing their genomes. Right. 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 and push certain cancers that are close to the edge if you will over the edge.

1:16:17So 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 on to 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.

1:16:54So that's part of a innate immune function, but there's pretty good experiment 11. 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.

1:17:33You 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.

1:18:12But 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 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 PD1 and a body -based therapy much more effective.

1:18:53So, we're going to try that idea in human beings, basically taking so -called oncogene -targeted therapy, backbone treatments, and then using what are called alkylating agent chemotherapies, which are the ones that can introduce new mutations most commonly. And even at somewhat low doses, it would appear you potentially can introduce the mutations without having some of the dilataries effects that chemotherapy drugs are well known to cause. Keith, I'm going to change gears for a moment only because I know we have a very short clock today relative to how long you and I could normally speak. And I want to talk about another very important topic.

1:19:23So 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 into, 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 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 gonna be alive in five years?

1:19:5860, 70 % of them? Yeah, that's about right. Yeah, again, it depends on the size of the patient 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 gonna 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.

1:20:35And if you wait to 10 years, it's none. What's a decent explanation for that observation? Which, by the way, if we had more time, we could tell the same story for every cancer, basically. In other words, what I refer to as microscopic residual disease, 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. Yeah. In other words, why does it work when you have hundreds of millions or billions of cells not all clumped together but sort of diffuse, but when you have like a hundred billion cells and they're like in big visible clumps, the same drugs just fail.

1:21:09There'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 have all, 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.

1:21:45You 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.

1:22:21And 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 overt menacides 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 colonel heterogeneity, the other is the secondary immune response concept, right?

1:23:01That basically all successful curative cancer therapies actually do trigger immune recognition through what's referred to as immunogenic cell death. So that you're killing the cells directly with your drugs, but that the mop -up work, if you will, of actually eradicating every last single cell is the immune system's job. It 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.

1:23:38And because we've directly demonstrated that like better immune recognition in patients who are receiving these therapies looking at biopsies compared to pre -treatment and that that happens rather quickly, you know, I think it's reasonable to them to be able to 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 is ultimately an immune system phenomenon. And I think there's kind of a hybrid there, too, right, Keith, which is that in the micro -metastases environment in the adjuvant setting, you have less capacity for the tumor to create the hostile environment in which to impair the immune system from mopping up the damage.

1:24:23It all favors keeping the cancer cell on its heels. And the way to do that is to just have as little of them as possible is going to increase our odds. You still have to win. I mean, you still have to kill because if you don't, it will get back onto its toes. That's right. I mean, this is what we're talking about is behind this, you know, massive wave of enthusiasm and its legitimate enthusiasm, I'm not hype. That early detection is going to allow our same toolbox of drugs to be massively more effective. That's the only reason I posed the question. You're taking the cue and you're running with it.

1:24:55Right. 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 pretty be vaccine. That's right. Exactly. But cervical cancer screening absent a vaccine is quite effective. So that's one. Breast cancer, for sure. We can cut the risk of breast cancer death by about a third with mammography. That's not a very inspiring number. I mean, I absolutely suggest that everyone who's eligible who you care about, you should strongly insist that they get mammograms.

1:25:32Coenoscopy 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, I'd say, lots of controversy, prostate cancer screening is really quite poor. It's almost like just non -randomly assigning people to get prostate biopsies, you know, getting PSA tests, basically. It's not a great way of detecting cancers and certainly not potentially dangerous prostate cancers.

1:26:08But 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.

1:26:50Yeah. 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.

1:27:38Furthermore, 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.

1:28:25Because that's sort of like saying, you know, there's too many fatalities in cars we shouldn't drive. Just doesn't make any sense. It's like, yeah, there are fatalities in driving. let's figure out ways to drive better. You can put a seatbelt on, you could not drink while driving, and you could mind the speed limit. That's a totally different situation than saying, we're gonna abandon all those things. So, you know, you're reminding me that I, in my world, 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 on that need.

1:28:59And it's into that massive on that 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 to 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.

1:29:42So kind of analogous to your PSA velocity example where you're sampling at multiple time points. If you sample at multiple time points now and subject those, I don't mean just to the methods that are being commercialized now, but are being commercialized. I mean, since we talked four years ago, what felt like very much a research method is now emerging as a real clinical option. There's methods now that can find cancers at an earlier point, and a broad array of cancers, like way beyond just the cancer types that we're talking about. The ones for which we have screening methods, I mean. So really, you know, almost pan cancer tests.

1:30:15But 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 Circuentumor DNA, as it's called, you can actually do more than just sequence for mutations to find that it's Circuentumor DNA is both 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.

1:30:53These 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, right, 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.

1:31:26So 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. We're basically, you know, we'd say, well, look, we see it in the blood.

1:32:00We 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, you know, 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 mechanisms The force fields the heterogeneity that we talked about before don't exist and so this is I mean a real reason for optimism I should just highlight that there's two applications here One is actually to do much more precise Therapy in the post -surgical setting so really figuring out you know right after surgery Who still has microscopic disease in them who doesn't that's a much easier problem I mean I actually talked to with Max Dean about that problem and And he's one of the pioneers in that field.

1:32:51And 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. Oh, no, no. If you solve this problem, you win the game.

1:33:25We'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 -searchical 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.

1:33:55What's the state of the market today, Keith, in terms of tests that people listening to this can actually get as part of a cancer screening protocol? So, Grail has a commercially available kit. It's not over the counter, you need to get it through a physician. What are some other tests out there? in your view how close are we to these tests being an imperative part of cancer screening? I think we're not quite at the imperative point, but we're certainly at the point where I would say it's reasonable to get a test. If you consider yourself an early adopter and you know who you are, it's reasonable to get a test.

1:34:29And 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 currently 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 -radio -graphic assessment, you don't find the problem, and that basically the medical community, because we're not talking of an oncologist who are doing the test.

1:35:10The 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.

1:35:42We'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 of blood. If you're 100x better than 10mal 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. 10 ml is exactly. Exactly. That's the point.

1:36:14And 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 a much bigger section of the population. It's a little hard to estimate right now, at least. Okay, 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.

1:36:45That's sort of our view of aggressive cancer screening in general. But when we use it, we do use Grail. And that's largely based on the affiliation with Illumina, which is if you've got the best sequencing company in the world that created the engine for this thing, then that sort of makes sense to me. But what else differentiates these companies? I mean, there's three kind of aspects to circling to 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.

1:37:15So 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 your 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 and then that methylation aspect that I talked about before that's the other feature that has been a differentiator in terms of kind of the first marketed products in this class, even across these three companies, but there are 10 more companies coming right behind.

1:38:01So basically, the first one is kind of not valuable for pan -screening because that's how you're checking for recurrence when you know the mutation, right? I mean, we're not going to be able to screen people on the basis of guessing cancer mutations, are we? Some would argue we can. I mean, 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 pick a number. You know, the thousand most common cancer mutations, the 10 ,000 most common, the hundred thousand most common cancer mutations that we actually can...

1:38:33Yeah, I mean, I guess if you had K -RAS and you had... P53. Yeah, P53 and B -RAS. P53 is mutated in 50 % of all cancers. Now, the problem is... The problem is there's hundreds of different mutations. 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 -surgical setting. You alluded to that, but just to make sure that people understand that that tech. Yeah, 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.

1:39:06And that's what's being done. And commercially, are these bespoke assays based on what comes out in the surgical specimen? But when you don't know what you're looking for, the argument is if you do enough sequencing, you'll find them. Are there companies, or is that all done in the lab right now? or 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, like we need the diagnostics, we can't even think about therapeutics until we basically diagnose.

1:39:47That'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. 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.

1:40:19So 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 know, you're going to point me in the direction of where there's a clinical trial that's promising.

1:40:57Not just a phase one that's like probably got no hope, but here's phase two that really has some hope. Okay, so there should be an entire industry of Keith Flaredies 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 that 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.

1:41:41And therefore it does matter who you know. It does matter which expert points you to the best treatment center. Because I can't clone Keith and a dozen other people that I know that I can pick up the phone and call. What does that look like? What can somebody do when they get that bad news? This drives me crazy what you're talking about in terms of access to expert opinion when you need expert opinion, and particularly for complex unique outlier cases, if you will. 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.

1:42:17Break down the silos of hospitals and centers and universities and whatever. And pool our, you know, kind of opinions. That's point number one, point number two is we need to leverage technology for this purpose. Like, people get all excited about artificial intelligence in terms of how it's informing chemistry advances and the like. And, you know, I'm excited about those things too. And then other aspects of biology discovery and all that. But this is the most obvious use, basically, right? Is that 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.

1:42:52And 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 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.

1:43:27Everybody'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.

1:43:58And you shouldn't have to get on an airplane, never go see anybody, but even on the zoom screen. I mean, honestly, this is, we are so inefficient in terms of how it is that we disseminate information. It drives me crazy. There are very few entities, but are a few working on this problem and kind of see it this way. You throw some technology, 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.

1:44:33There'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. Yeah, it's not the full insight machine. That's right. But it's going to come. I mean, this is another area that I'm under invested. We'd really like to see this because we otherwise, as you know, we're kind of blowing the bank on a very efficient system as it stands right now and it's not scalable, certainly not globally scalable. Well, Keith, this was fantastic. Obviously, we're going to sit down in four years again and talk about the last four years, which will be going forward from here.

1:45:03And 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 Metaboloc ones you mentioned.

1:45:32Totally agree. The good news is that technology curve continues to bend upward, right? And so we We talked about sequencing technology as an example there, but cell engineering advances ability to take new molecular targets and rapidly cycle that through to new drugs, small molecules, antibodies, the like. All of these advances are converging in a way that if we keep talking at four -year increments, the pace of progress is going to be substantially greater per unit time. We've already witnessed that. There's no question that four -year increments over my career, that's been true. It's reflected just in approval of drugs by the FDA for cancer.

1:46:09But 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. 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.

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