Following a brief refresher on the immune system, Dr. Marron discusses how Mount Sinai is using immunotherapy to treat solid tumors and moving the bar through research and clinical trials to improve outcomes for patients.
Good morning. My name is Megan. I'm one of the medicine chief residents and today I have the pleasure of introducing our speaker, Doctor Thomas Marin. Doctor Maron is the director of the Early phase Trials Unit at Tish Cancer Institute and a professor of immunology and immunotherapy, as well as professor of Medicine, hematology and medical oncology at the icon School of Medicine. He holds a phd in immunology and is a prac practicing thoracic medical oncologist. His research program focuses on the development of novel immunotherapies and combinatorial therapeutic approaches for solid tumors. He leads a translational oncology bench to bedside to bench program in partnership with Maria Mora and her laboratory focused on developing novel therapeutic approaches and repurposing available biologic therapies. Please join me in welcoming Doctor Marin. Thank you so much. It's always a pleasure to come home to Department of Medicine grand rounds. Uh I'm gonna give a little bit of an update on uh uh cancer immunotherapy and how we're using these now to treat solid tumors as just standard of care. And then I'm gonna talk to you about some of the research that we're doing to try to uh move the bar somewhat so that we can improve outcomes for our patients. Uh These are my disclosures. I'm a phase one doctor, everything I say is off label. So do take it with a grain of salt. Uh So I always like to take a step back when we're talking about immunology because my, my father tells me that immunologists talk in their own foreign language. Um And it's good to get everyone on the same page going back to medical school and, and really thinking about the immune system as this dichotomy between the adaptive and innate immune system. And both of these are extremely important for, you know, uh defending us against microbes, but also for defending us against cancer. And, and they're also being hijacked by a tumor in a variety of ways. You'll see, I'm gonna discuss all these different players, both the adaptive and the immune system thinking really about your T cells and your B cells and the humoral component of the immune system, as well as the innate immune system, which is really the focus of a lot of our work. Um specifically looking at uh phagocytes, both neutrophils and in particular macrophages, which make up a good chunk of the tumor and within our body. And in a, you know, sort of an evolutionarily conserved way, there's this very delicate balance between activation of the immune system, hopefully against foreign antigens and a variety of tolerogenic signals that really keep our immune system from attacking, uh, our, our normal tissue, obviously, tolerogenic signals are what's happening 99.99% of the time because we're not constantly being exposed to foreign microbes or cancer. But as we get older and as we hang out in the sun and live in New York City and smoke cigarettes. Hopefully, no one here, uh, we have this process of carcinogenesis where you're developing more and more mutations in our tissue all throughout our body. And many of our, our cells are actually looking more and more foreign and more and more recognizable to the immune system. And every cancer is caused by mutations. This is at the heart of any sort of malignancy changes in your DNA. And uh a very small subset of mutations actually result through uh translation and transcription and translation into mutated proteins. And these mutated proteins are what actually make a cancer cell visible to the immune system because it's the one thing that really differentiates a normal cell uh from a cancer cell. And it's uh these mutated proteins are what we call neo antigens are things that your body hasn't been tolerated against in your, in your thymus and through normal tolerogenic mechanisms. And the way that your immune system is taught what to recognize is really through antigen presenting cells and particularly the dendritic cells, which are the most potent cross presenters of antigen, the most potent antigen presenting cells. I always call them the Professor cells of the immune system. And we have dendritic cells all throughout our body and our brain and our skin and our guts. And they're constantly sampling the micro environment, making sure that there's nothing to be concerned about and figuring out if there's any antigens that they should be, you know, alerting the immune system to. So your dendritic cells are constantly taking antigen from dying cells, whether that be pathogenic death or just normal turnover, they're internalizing these. And at the same time that they're taking an antigen, they're sampling the micro environment using a variety of innate immune receptors like tola receptors, both on the cell surface and in the endo zone. And, and that's really telling the uh dendritic cell if there's any sort of alarm signals that they should be aware of, or if this is just normal cell turnover, and you really should, you know, exert a tolerogenic signal. And these dendritic cells then traffic antigen either through direct presentation to MH C class two or cross presentation to MH C class one. And this directly presents these antigens to either CD four or CDT cells respectively. And at the same time that you're seeing this, this uh sort of interaction through the MH C and the TCR complex. It's really this signal two which is actually a slew of different signal twos, but it's the second signal, not the signal that, you know, this is the antigen. It's the signal, whether or not, this is something to be worried about. And so really if you're having an alarm signal, like if the, the dendritic cell is sensing bacteria or viruses in the micro environment, then they'll upregulate signals that will activate T cells against foreign antigen. So, if our immune system is able to recognize foreign antigens, why aren't all cancers immediately removed from our body? And typically they are. So everyone in this room right now probably has lots of cancerous cells in their body. And by the time you get to dinner, those are all gonna be gone. And tomorrow morning you'll have all new cancers. The problem is that eventually you'll have a cancerous cell, particularly as you get older, that's really able to evade the immune system. And it does this through a variety of mechanisms. Uh One of the mechanisms that we know most about because we have therapies to, to disrupt it is something called PDL one. So this is program death Ln One. It's basically a stop sign that cancer puts up and says, hey, I know you recognize me but don't attack me and it turns those T cells off even though the T cells have been adequately taught what to recognize. And uh the way that we un hijack the immune system is we really disrupt these off signals and we'll go through, there's a bunch of different off signals, but PDL one is one of them and we have a variety of therapies that are FDA approved, that you're seeing uh people in the hospital with the uh the bad sequela of um that, that turn off this off signal and really allow the immune system to do its job and kill the cancer. So checkpoint blocking antibodies, they, they really revolutionized the, the care of cancer patients and in some cancers, they're, they're, you know, curing previously incurable cancer. Uh Everybody has heard of these at this point. You know, one of the most famous uh people to have received checkpoint blockade is Jimmy Carter. It's his 100th birthday today. Thanks to his anti PD one therapy. He was cured of metastatic melanoma to his brain over 10 years ago. Uh People all know about these also because they advertise them constantly on Monday night football and everywhere else under the sun and they have all these ridiculous names that no one can pronounce. And you think based on the advertisements with grandmas running through the fields that we're, we're curing everyone and we are curing some people. And so this is one of the first studies that came out of the uh Melanoma group at Memorial Sloan Kettering. They were looking at Melanoma patients with metastatic Melanoma which had a um uh average survival of less than a year. And this was a uniformly fatal diagnosis. And here they randomized patients to receiving dec Carba zine, which is a chemotherapy that no one in this room that's training has ever heard of because we don't use it anymore. Uh It's a very bad chemo, very toxic chemo. I gave it once as a fellow to an inpatient. Uh so they either got to Carba or Novum, which is an anti PD one you can see here, these Kappeler Curves split in a really nice way, much better than just about any other therapy we develop in medicine and uh additional therapies have been developed uh and added on to novo. So now a standard care for metastatic Melanoma is Nivolumab and Hippo maab uh which is AC TL A four antibody. And, and here you can see they have really impressive improvements in survival and the most exciting thing about these Kappa Meyer curves. And, and again, this is a universally fatal diagnosis back in 2012 is that we're seeing plateaus form and when you see a plateau form on a Kappa Meyer curves, it means you actually might be curing some of these patients and we still are always hesitant to use the C word cure uh with our patients because we don't want to guarantee them anything. And this is something that we weren't used to doing with patients with metastatic disease. But in, in 2024 we're actually curing about 50% of patients with metastatic melanoma. And I, I'm technically a lung cancer doctor along with being a phase one doc. So on Fridays, I see lung cancer patients outside of clinical trials and I give them a combination of chemotherapy and pembrolizumab. So chemotherapy, th this was the trial that set that up. And in red, you see, with chemotherapy, the immediate overall survival similar to Melanoma was less than a year. But when we added on pembrolizumab, we more than doubled the survival of those patients. So it means our clinics are more than twice as full as they were in the past. Super amazing to see these responses. Um But unfortunately, I'm not retiring anytime soon because the majority of our patients are still dying of this disease. And really uh is one of the reasons why we're, we're working in the lab and in the clinical trials program to improve on these therapies that we've been developing. So um there, the issue is that I I showed you that one stop sign that can, that cancer puts up the PDL one. The issue is that there is a whole slew of different stop signs and go signs within the tumor micro environment. And you know, we have drugs that target just this very small corner of the immune response against uh cancer antigens. But there's a slew of these on and off signals. Really the on signals are, are activating your T cells, your natural killer cells, your your moral immune system, your macrophages to kill cancer. And then there's all these off signals and these are tolerogenic uh mechanisms that are really evolutionarily conserved. This is part of the way in which our body doesn't have, you know, massive autoimmunity and inflammatory diseases at all time. Um But these are a lot of the ways in which cancer hijacks the immune system is, they upregulate these off signals and they down regulate the on signals. And along with, you know, these drugs for PD one and CTL A four, we have clinical trials here at Sinai and elsewhere as well that are targeting a slew of different on and off signals both within the tumor micro environment and also within the the interaction and that education synapse between T cells and antigen presenting cells, which as I said are kind of the professor cells. And if you zoom in just on this little synapse right here, you know, we have a slew of these receptors and ligands and it's really the the constellation of all these on and off signals that tells the T cell whether to turn on or turn off. So this isn't a black or white thing. It's really 50 shades of gray and all of a sudden you're gonna be more towards on or more towards off. And that's what's gonna kick off uh A CD A T cell to be cytotoxic versus exhausted and then attack its target. So, therapeutically, we can modulate these on and off signals. Uh the the drugs that we already have that are FDA approved are really antagonistic antibodies. So these are negative receptor lian interactions. So by developing antibodies that sort of separate those and block that justly inhibit that interaction, you turn off one of the off signals so that the on signals outweigh the off signals and you're able to activate your T cells. And conversely, we can actually use agonistic antibodies. So here you want these receptors and ligands between the T cell and your, your antigen presenting cell, like your dendritic cell to interact to turn on both A PC and the T cell. And here you can use antibodies to kind of mimic the interaction. So you're sort of tricking the T cell um who is expressing CD four L and to thinking that they see a CD 40 that turns the T cell on or vice versa. So, uh this sort of manipulation of the immune system is really at the heart of all the cancer immunotherapies that we've developed. Um just AAA brief word since it's very applicable to all of our uh medicine colleagues is that um checkpoint blocking antibodies, they, they do have significant risk. And, and these are the risks that oftentimes we're seeing in the hospital. I have a patient on nine West right now with pretty serious pneumonitis. And what happens is, you know, if we're either taking off these stop signs, we're taking our foot off the brake or if we're stepping on the gas, what can happen is that you can develop uh inflammatory reactions. Uh These aren't specifically autoimmune per se. Some rheumatologists don't like us using that, that terminology. Uh I sometimes call it auto toxicity. There's a variety of different mechanisms of inflammation that can result and we can basically give you an itis of any part of your body. And so I, I've probably given hundreds of different itis at this point with these therapies, all of these side effects are extremely rare, uh which also makes it hard to predict who's gonna have them. And it's also very difficult to uh study how we treat them just because they are so rare and their timing is so varied from one patient to the next. And you can have a patient who can get one of these itis three days in typically, it's, you know, 8 to 10 weeks that patients develop these. But I also have had a patient that developed nephritis 18 months after starting pembrolizumab. So it's very unpredictable. Uh One note that I always like to tell patients as a silver lining if I end up having to hospitalize them. Uh is usually if these patients develop immunotherapy related adverse events, these tend to be the patients that actually do the best. So there's been many studies across many different tumor types that the data is not perfect. And there are some negative studies. But you know, our group uh uh where we have one of the largest HCC programs in the world outside of Asia, we looked at our cohort and combined it with uh a group from Imperial and from Dana Farber. And we saw that the liver cancer patients who developed immunotherapy related adverse events had a much better uh progression free and overall survival. We actually validated this with a large FDA cohort. So I do think I always uh try to put a silver lining and I give patients a high five as I send them to the emergency room for their colitis or pneumonitis or what have you. So maybe their cancer is gone. So, as I mentioned, you know, it's, it's super fun uh being able to cure patients every once in a while and definitely keep them alive longer. But uh the, the goal of our, our work is really to figure out how we can cure more people. Obviously, our, our goal is 100% not 20%. And this is my current treatment paradigm for uh lung cancer patients who don't have driver mutations. So these are typically the smokers that come see me um with metastatic cancer and we use PDL one staining, which is just an IHC staining for how much of that stop sign is on the tumor to dictate. You know, what cocktail of uh immunotherapy and chemotherapy or double immunotherapy, we might give patients and like I said, you know, we're more than doubling the median overall survival of our patients, which is uh super gratifying. But um we obviously have a lot of room for improvement And as I'm an immunologist, my focus is entirely on finding other ways to harness the immune system. And we're really doing uh two approaches. So one approach is to find new ways to induce de novo T cell responses. So if you give somebody a drug that takes your foot off the brake, but your car is on a flat surface, the car is not moving anywhere. So if you haven't taught your immune system what to recognize if you haven't had a vaccinal effect and educated your T cells, what to recognize. You take your brake off that T cell and it's just gonna sit there and not do anything. And so a lot of the uh approaches that we're doing and we're, we're opening a bunch of uh moderna vaccines where we're using neo antigen vaccines to induce de novo immunity. And that's particularly important for patients who have PDL one negative tumors. So that's really a marker of patients that don't really have any recognition of their cancer. We can also use CTL A four blocking antibodies like luma to induce Genova T cell responses. Those come with a lot of toxicity though. Um And so it's always a delicate balance, but the one thing is we have to induce, you know, a new immunity, we have to teach the immune system what to recognize. But even if you do that, sometimes patients don't respond and what our work really focuses on is harnessing the rest of the innate and adaptive immune system. Because if you take a tumor out, if you take a lung tumor out and you cut it up and you look at it under a microscope, sometimes there's actually more immune cells than there are tumor cells, which really underscores two things. One, you know, this is obviously a disease of the immune system if there's that many immune cells there. And the other thing that's really striking is if you look at the immune cells, you know, all of our therapies that are FDA approved to date and probably 90% of them that are in development are focused on your CD A T cells, which are your, you know, targeted uh cytotoxic T cells, but the majority of immune cells are actually myeloid cells. So they are neutrophils and macrophages. You don't even see the neutrophils here because they're hard to study. Uh but macrophages make up about a half of the cells uh that, that we see when we cut out a tumor and we look at it under the microscope and we know that these macrophages are not the normal macrophages you see within tissue. So these are not tissue resident macrophages, like alveolar macrophages in the lung or cooper uh cells in the liver. These are actually monocyte drive macrophages and this is work that's really come out of Miriam Mora's lab. She studies ontogeny of these cells and, and they've really beautifully characterized this concept of emergency myelosis. So, emergency myelosis is basically when your bone marrow gets revved up due to some sort of emergent stimuli. So, infection like COVID causes emergency myelosis. That's why everyone had so many myeloid cells that led to the massive inflammation that we saw in our patients, particularly in our older patients who have basal emergency myelosis. But emergency myelosis is also a response to stimuli from cancer cells. And it's actually one of the many ways in which cancer is really hijacking our body and taking over our immune system. And the, the theory, I'll show you some of the data that supports this is that cancer is really secreting a variety of, of cytokines and chemokines into the blood that traffic to the bone marrow and basically hijack the bone marrow and they lead to this emergency myelopoiesis, meaning it's an expansion of your myeloid progenitors. In particular, these immature myeloid cells are then dumped into the blood and they traffic into the tumor where they set up shop and they're really polarized into bad myeloid cells. So these tumor associated macrophages or monocyte drive macrophages, which are extremely immunosuppressive and really turn off the T cell benefit. So even if you taught a T cell what to recognize if you have a tumor that's chock full of very immunosuppressive macrophages, those T cells aren't going to be able to do anything. And we've been studying these macrophages for a while and, and many people have tried basically just to deplete macrophages from the body. And that doesn't really work because you're kind of throwing the baby out with the bathwater because macrophages are one of your most antigen important antigen presenting cells. They're extremely important for anti tumor immunity also. So you can't get rid of the good and the bad. And we really focused on trying to identify very specific programs and phenotypes of the bad macrophages so that we can learn how to either deplete those or potentially re polarize them and turn them from bad guys into good guys. And we've done extensive single cell analysis of untreated uh human non small cell lung cancer. And we see very similar programs in colon cancer and liver cancer. Basically everywhere we've looked and, and what we see is that they're the very immunosuppressive monocyte drive macrophages when you look at their transcript omic signatures. So, transcriptome means we're looking at the RN A and you know, every cell in your body has the same DNA. It's really the RN A signatures that tells us about the, the functional specificity of those cells. So we can identify the monocyte drive macrophages from their very, you know, immunosuppressive phenotype. And then we look at other signatures within those those cells to see how we might be able to target them. And one of the things that we see is there's this very strong il four signaling signature within these cells seems like these cells are somehow being polarized by the cytokine il four. And it's activating this whole downstream pathway from the il four receptor. And interestingly, we look at a mouse model. This is the Myriam key P model. So this is Kras mutant P 53 deficient lung cancer in mice. It's kind of like uh we're having our mice smoke cigarettes because it looks very similar to what we see in uh smokers. And interestingly, they also have this very strong ale four signaling signature. And as I said, we're also very interested in dendritic cells. These are the professor cells of the immune system. And so we've done, you know, really exhaustive single cell analysis of uh human lesions as well as these mouse lesions. And the pink is human and the brown is uh mouse, these are all individual uh dendritic cells, each of these rows. So what we can do is we can identify the different dendritic all subsets by looking at their transcriptome signatures. And we can see these DC ones, this is the most potent cross presenter of antigen uh to the immune system. These Miriam's lab about 10 years ago showed are absolutely necessary for response to nivolumab or pembrolizumab. All these fancy drugs I've been telling you about. So if you don't have these, you don't respond to checkpoint blockade. So we identify these DC ones. DC twos, we still don't really understand what they do. So we're, we're working on that but one other subset of dendritic cell is a small subset. But we see it in both humans and in mice and we see it across all tumors that we've looked at so far are the, is this population of dendritic cells that you can see here from the, the transcript stomach? This RN A signature looks totally different. You don't really have to understand this plot to see. This group looks different from this group looks different from this group. So this group, these MRD CS look very different and we call them MD CS um because of their, their functionality and what we were able to do is we were able to use a MO we had GFP labeled tumors. So these are basically green tumors. And so you can actually see which of the dendritic cells have gobbled up tumor antigen versus those that have gobbled up normal antigen or haven't gobbled up anything at all. And if you look at the uh dendritic cells that have taken up the green antigen, so we can sort them and say what's green and what's not green. But what we realized is that those green ones really are these Emeric D CS. And so the Emer D CS really represent dendritic cells that have already successfully sampled some antigen, specifically tumor antigen. And what you're seeing is these dendritic cells have a very strong upregulation of a maturation uh signature which that is normal. When dendritic cells take up antigen, they mature, they stop eating and then they start processing it. Um They upregulate regulatory markers and this is uh again, uh a normal homeostatic mechanism because most of the time, 99.99% of the time when you're laying your hand cells in your skin are sampling antigen. It's just your own skin antigen and you, you want them to tolerate T cells against that because otherwise you're gonna get all the scary epics and you know, inflammatory diseases that you have within your skin. Um So cancer really should be activating these dendritic cells. But the den the cancer is really able to co opt the system and and induce this regulatory tolerogenic phenotype. But interestingly, we also saw this very strong type two signature. So I just showed you that these monocyte macrophages, the bad guys have the strong il four signature, il four is the, you know, canonical type two cytokine. And here we also see lots of il four receptor alpha and other members of the type two signaling pathway. So when I'm talking about type two immunity, uh what exactly does that mean? So um in general, we always like to make things black and white and they're never quite that simple. But you know, back in medical school, I learned about type one immunity and type two immunity and type one immunity is super important for anti viral responses. So, anti COVID anti cancer responses. Well, type two immunity historically and evolutionarily was very important for anti helminth responses. But because we use so much Purell and bleach here in New York, we don't have a lot of helminth challenging our type two immune system and sort of the cornerstone of the hygiene hypothesis where we're not being exposed to all these helmets that we would have been back in the day. Now, you sort of have aberrant activation of the type two immune system and that's why we have all this at that. We now see um in patients particularly in Children. So this is the reason why kids can't have bake sales anymore because your type two immune system has gone haywire. But we also know that, you know, while type one immunity is very important for anti tumor immunity seems like type two immunity is very pro tmo aic. And this is uh a concept that's been known for decades. At this point, this is just some data looking at patients with pancreatic cancer. So these are patients that are not getting immunotherapy or anything, they're just getting chemo. And we know that patients and this is seen in pancreatic cancer, breast cancer, lung cancer patients who have a stronger type two signature, systemically, more uh type two cytokines. Like here, we're showing il four and il 52 canonical type two cytokines. If you have more type two cytokines in your body, your cancer grows faster and you do worse. So we knew that, you know, type two immune responses really pretend worse survival and really help cancers grow and metastasize. And some of the, the most important preclinical work has come from Lisa cousins, who's the, the immediate past president of the AC R and, and her group about 15 years ago, published this first paper where they uh were looking at a breast cancer model. Again, this is mouse data, but they basically took tumors out. They looked at those T cells in the tumor and they saw that those T cells had a very strong type two signature. So they make again lots of il four and not enough interfering gamma. So this is the type one cytokine. This is the type two cytokine. So you seem like you're having AAA tilting towards the type two end of the spectrum. And interestingly when they either blocked the or they knocked out the il four receptor and it's the il four receptor alpha which disrupts not only il four signaling but also il 13 signaling, which is another type two cytokine, very important for a variety of at topic conditions or if they use a neutralizing anti il four, you actually see a significant decrease in the growth potential of these tumors and the metastatic potential. So, uh what does this have to do with treatments we're giving breast cancer patients? So they then looked at uh the, the standard therapies for breast cancer at least back in 2015 which were really just radiation and chemotherapy. And they actually saw that um anti Il four synergize with radiation or chemotherapy. So it seems to rev up the response to these uh uh very toxic stimuli to increase the likelihood that we're able to cure. Uh or at least eliminate or slow the growth of tumors. So, these are old fashioned ways of treating cancer. I always try to avoid radiation and chemo when I can because they're very toxic uh and much more toxic than immunotherapy. So we wanted to say what happens when you give immunotherapy and you block I four. So we use this uh KP model that I mentioned earlier, kind of like a smoking model on mice and, and these mice really don't respond at all or this tumor really doesn't really respond at all to checkpoint blockade. So it's a very resistant tumor and many of our patients have primary resistance to these therapies. Uh But interestingly when you take these mice and you give them anti I four, it significantly decreased the growth potential of these tumors. So we're just neutralizing a cytokine and all of a sudden the tumor is not growing but the, the cancer immunotherapy doesn't do anything. And when we look at a slightly more immunogenic uh uh tumor type, which is a KP one, this is a, a mouse uh uh cancer line that does respond a little bit to checkpoint blockade. Um But it, it also responds to IL four blockade and these actually synergize to result in a very impressive anti tumor immunity. So I, I promise you we'll get to humans in a second. I am a human doctor and a mouse doctor, but we, we wanted to dive a little more into saying what exactly is going on because if we can understand mechanism, we have a much better chance of actually, you know, uh translating these findings into humans. So um why is there all this IL four, you know, these are not patients who have eczema or allergies? Like why, what, where is this IL four coming from? What is it acting on? How is it sort of disrupting anti tumor immunity? So uh I'll take these questions in reverse. First of all, you know, what is it acting on that? That helps us find out where it's coming from. If we can find out where it's actually acting on. And, and I showed you the dendritic cells, the professor cells of the immune system seem to be very responsive to Il four. So we figured maybe in the tumor, if we take the tumor out and look at it, there's lots of il four there and it's acting on the dendritic cells. And that's what we would have guessed. That was our hypothesis. But when we knock out the il four receptor alpha from all the dendritic cells in the body, see here, getting rid of the il four receptor doesn't really decrease the growth potential and we also knocked out il four receptor from all the other tissue resident immune cells, like the alveolar macrophages and the T cells within the tumor. And we didn't really see any impact on tumor growth, which was really counterintuitive. We figured there must be a lot of il four in those lung tumors that was driving things. So, um, we, we, we obviously had already known about this concept of emergency from myelopoiesis. And we figured, you know, I wonder if the problem is not in the tumor, it's actually in the bone marrow. And we know that cancer is really a systemic disease, even if you have stage one cancer that's localized in, in your lung. Your cancer is hijacking your whole body. These patients are inherently immunodeficient the, the day that they get cancer. And so we looked way upstream. So we were looking way downstream at the, the mature dendritic cells. We looked way upstream at the granulocyte monocyte progenitor. And uh we did this with Florence J. He was uh a postdoc in Miri Moran's lab when I was doing my phd about 20 years ago. Um and he developed this amazing model where we're able to knock out il four receptor alpha very early on in myelopoiesis. So we can knock it out from these GMP cells. So these are sort of the stem cells that lead to monocytes and neutrophils, which we know are kind of the, the two bad guys within the tumor micro environment, if you will, and if you knock out a four receptor alpha very early on, you see a significant decrease in the growth potential of these tumors. But then we looked just downstream and knocked it out of either the monocyte progenitor or the neutrophil progenitor. And we really didn't see any impact on tumor growth. So this basically is telling us that there's a very important moment in time and differentiation of your macrophages and your neutrophils very early on in myelosis where we believe that there's some sort of imprinting happen. So we think that these GMP cells are being exposed to il four very early on. And that's somehow driving this emergency, myelo poesy imprinting on your immune cells and, and, and, and getting them sort of setting them up for the, the um bad uh future that they have when they're hurt to the tumors. And indeed, you know, if we look at these mice that don't have a L four receptor alpha very early on, if they don't have a tumor there, it doesn't really affect their myeloid cells. So you see the exact same number of these stem cells in their bone marrow, uh no change. But when you give them a tumor in normal cells, you see this emergency myelosis, you see expansion of your myeloid cells that are dumping those monocytes into the blood that are trafficking into the tumor. But you basically lose that. If you knock out the il four receptor. So it really suggests that il four is one of the key factors in driving this whole concept of emergency myelopoiesis, whether it be in response to AAA toxic stimuli or cancer. And indeed, when we then look downstream, if we knock this out way upstream, if we look downstream in cancer bearing mice, you really see imprinting on the monocytes once they get into the blood and imprinting on the monocyte macrophages, once they're in the tumor. So it seems like something's happening very early on in myelopoiesis. That's, that's then setting up for this entirely immunosuppressive microenvironment within the tumor. So it just sort of uh talks to you about the, the, the access between the tumor and the bone marrow and how the tumor is really hijacking the bone marrow very early on in cancer development probably before we can even detect the cancer on cat scans. So, uh there seems to be a lot of IL four doing something bad in the bone marrow. So, where is this? Il four coming from? And so we looked at using a GFP reporter mouse at all the different cells within the bone marrow and all the things that we thought might be making il four like T cells, B cells, ILC two didn't see any il four, but the, the type two granulocytes. So, eosinophils and basophils, these are granulocytes that we usually choose to ignore because they're very difficult to study. Uh they, they actually were making all the A L four in the bone marrow and, and you know, none of these cells were making il four in the tumor. Interestingly, it was only in the bone marrow that we're seeing this. And I didn't actually realize this. But um up to 5% of the bone marrow are these type two granulocytes. So your, your bone marrow is chock full of eosinophils and basophils. And interestingly, when we specifically looked at the basophils, we saw that the basophils here in green were hanging out right next to the hematic progenitors in cancer bearing mice. So basically, as soon as a mouse got cancer, all of a sudden, the basophils were sticking to the GMP cells and they appear to be pumping out IL four and telling those g uh the GMP cells to expand and then go to the tumor and set up shop. And indeed, if you get rid of basophils, tumors don't grow and you don't see the same sort of emergency myelosis. So it seems like this is uh using an anti CD 200 or three. So this basically depletes all the basophils from your body. When we deplete basophils from the body, these tumors don't grow. So this is our sort of working hypothesis is that you have these uh type two granulocytes, eosinophils and basophils in your bone marrow, they're getting revved up by cancer stimuli. Um They're, they're then secreting a lot of il four. This is polarizing and expanding your myeloid progenitors. These dump monocytes into the blood, they traffic to the tumor, they set up shop and they really allow for tumor growth and tumor metastasis. So final mouse uh question is why are the basophils making so much ale for them? That's a little strange. You know, what is it that's coming from the cancer? We think that there's these secreted factors. And indeed, you know, if you take basophils and you either incubate them with media from tumor bearing mice or, or non tumor bearing mice, you see that that's really what makes the basophils make ale for. And interestingly, if you grind up a bunch of uh uh lungs that have tumors versus normal lungs, we saw there were eight different cytokines and chemokines that were significantly upregulated in the tumor bearing mice. So it really seems that um these might be some of the cytokines and chemokines that are leaving the tumor trafficking to the bone marrow and revving up the bone marrow. And I, you know, I looked at this data and we went back to some of our, our serum data from my patients and these are lung cancer patients compared to um controls. So just, you know, age match smoking controls. And we see that in their serum six of those eight things that we saw in mice we actually see in humans and we were excited about that. We were hoping that one of those might be the magic bullet. And if we turn it off, all of a sudden, we would disrupt the ability for tumors to grow. Um But interestingly, it's sort of this gestalt this cocktail of all these different cytokines that are being made by the tumor and trafficking to the, the bone marrow that rev up the bone marrow. So you need kind of this this mixture of different cytokines and chemokines to act on the basophils to make IO four and really drive this whole concept of emergency myelo coes. So again, these are our tumor signals that are are being secreted. They go to the bone marrow, they turn on your basophils, they make a lot of il four. You get the expansion of your, your uh GMP cells dumping of these immature monocytes that traffic into the tumor. And this is really a vicious cycle. This emergency melo poly that we'd find like to find a way that we can uh disrupt this so that we can um sort of hit the reset button on the tumor micro environment and allow the T cells to get back to work. So mice are great. I am not a mouse doctor, I am a human doctor. And so we, we saw this data and we got excited and we were very excited by this concept that maybe we could combine PD one blockade or PDL one blockade, which we're already giving to our patients. And unfortunately, in most patients that either doesn't work or it works for a while and stops working. We could combine that with IL four blockade and we could potentially see some synergy. So we don't have an A L four, an anti LL four neutralizing antibody. Uh But we do have a Il four receptor alpha antibody. So this is Dupilumab. Uh It's the only drug I think that's advertised more than cancer immunotherapy on television. Um And there are dozens of New England journal papers that are highlighting the use of dupilumab just in the last 5 to 10 years in a variety of inflammatory and atop conditions. And a lot of this work has actually been led by uh Mount Sinai. Uh both our G I group and also the, the chair of uh dermatology and her whole group have led to all of the approvals and at topic dermatitis. So we, as you can see here, we're giving it to uh kids, 1 to 11 years old. Uh This really suggests this is a very safe drug, which it is five of the people on my research floor use this drug uh on a weekly basis. Um really no side effects. And so we said, well, why don't we try this in our cancer patients? So we, we opened this trial uh a couple of years ago now where we took 21 of our lung cancer patients that were progressing on checkpoint blockade. So they had received checkpoint blockade and they either didn't respond or in most cases, they respond for a while and then they stopped responding. And our goal is to say, hey, can we hit the reset button and can we sort of turn off that emergency, myelosis for a few months and see if we can get your T cells to wake back up and kill the cancer. So here, all we do is continue this PD one blockade that now has stopped working. Uh We continue that and we just add three doses of dupilumab. Um And so this is the il four antibody. So it's the same thing that we're given to our allergy patients. It's basically an allergy medicine if you will. And what we do here is we always get a lot of biopsies and blood so that we can really see if we're recapitulating the biology that we see in mice. But in humans. And interestingly in the phase one B, this is just the first six patients that we reported um in this mechanistic paper uh earlier in the year, um we actually saw two of the patients had a really nice response. One of the patients um went into reinis. So he, he had uh uh squamous cell carcinoma. He received chemo radiation and was getting immunotherapy. And then all of a sudden he progressed and he had a new lymph node in the middle of his chest and his mediastinum and he had some retroperitoneal disease. As well. Very painful. All we did between this scan and this scan was give him three do. We just continued the drug he was already on. That wasn't working. We gave him three doses of D puma and his cancer started going away and he went into complete remission eventually. So this is uh very exciting. We weren't really expecting this. We were thinking this might be a better option very early on and maybe not an established tumors in patients, but they'd already had their, you know, immune system beat up by uh uh chemotherapy and radiation. And interestingly, when we take a look at the tissue, we also saw very significant changes and we actually strangely even see these in the nonresponders. So even patients that their cancer kept growing, we do see the dupilumab appears to induce very sys uh interesting systemic and intra tumor changes in the immune infiltrate. So here we're seeing basically formation of tertiary lymphoid structures. So in uh infiltration and organization of CD eight cells, uh dendritic cells, a lot of B cells coming in and, and in the blood, we're seeing similar things to what we see in mice. And unfortunately, uh it's very rare for us to actually recapitulate what we see in mice and humans because we're not inbred rodents. But here actually, we were seeing very similar trends where you were seeing, you know, a significant drop in the inflammatory monocytes. Again, there's only six patients. So very preliminary data and we see an increase in the effect of T cells. And we look at the cytokines uh using a very broad panel called the OING panel that we run in the Immune Monitoring Center. Um If we looked at blood on day, one day, four, so four days after getting the first injection and then on the day that they got their third injection, you see a significant early increase in key chemokines like CXCL 11, which are important for recruiting T cells and interfering gamma, which is a marker of a type one immune response. And by day 43 we saw a significant decrease in a variety of uh quote unquote bad uh cytokines, um like il one il six, these are members, il 33 members of the inflamma zone pathway that really regulate the ability for your T cells to respond to tumor antigen. And also by day 33 we see an increase of of key cytokines that are important for activation of T cells like il two il seven ill 15. So it seems like you the the the body and we saw this again in both, you know, responders and nonresponders is responding to this allergy medicine if you will, even though some of the patients cancer continues to grow. So, based on that study, we actually opened this other trial uh which is just giving some mims of the, the PD one antibody and do pili to lung cancer patients who are going in uh to surgery. So two weeks later, they could just get a single dose of this. And two weeks later, we cut their tumor out and we see if we're able to um induce sort of a vaccinal effect in these stage one patients because we know about 30% of them, 35% of them eventually recur. And we also teamed up with uh some colleagues at the Ontario Institute for Cancer Research. This is a surgical program led by uh a Doctor Arnaud. And, and she had seen our data and, and quickly opened this trial where they gave breast cancer patients, either a dose of PD one or uh PD one and uh IL four blockade. And they're gonna be uh presenting this alongside us. We're gonna both be presenting our studies at siti in about a month. Uh And so we're excited to see what they saw on breast patients. So we had this working hypothesis that there's these tumor factors that are hijacking your bone marrow and leading to this uh myelosis, potentially, we can block that with dupilumab. But II, I just told you, you know, not everyone's responding to this and, you know, everyone's cancer is different, everyone's immune system is different. And we never had the delusion that maybe, you know, everyone had a type two signature and we were gonna cure everyone's cancer. Um But it really does drive us to better understand the other potential therapeutic targets that we might look at. And, uh, this paper came out last week as one of our superstar MST P students, uh Matthew Park who's now back in his second year in med school. Um, and he, uh, was, he the, the paper has nothing to do with the story, I'm gonna tell you, but it, it really is about understanding aging and why aging really is associated with a low level of uh this emergency myelo poes. And as we get older, we get more and more inflammation and we're basically, you know, a sitting duck or a Petri dish for cancer if you will as we age. And it's a new understanding of the concept of inflammaging. But one of the things he, he did was he was looking in, in humans and in lungs or humans and in mice at their uh lungs, uh specifically their lung tumors or in the bone marrow. And he saw that these monocyte progenitors, the, the guys that we were very interested in um uh do make a lot of IO one beta, which we know is a bad thing for cancer. But there's also a lot of Il one beta that's made by neutrophils and, and uh a company uh Novartis had tried blocking IL One beta in probably about 10 different very large lung cancer trials and all of them failed. Unfortunately. Um but what Matthew also notice is that they make a lot of il one alpha. So I one alpha and is one beta are very similar cytokines, but they're not redundant. And they're both very key parts of the inflamma, which is sort of part of your immune system that leads to bad inflammation. So people always think inflammation is good because your immune system is attacking cancer. There's good inflammation and bad inflammation. I and alpha and Iowa and beta are, are really driving bad inflammation. They're important for response to infection but not for cancer. And if you block either of them independently, you don't really see any effect on tumor growth. But interestingly, Matthew then combined dyin alpha and beta blockade and, and he did see a response. So I saw this data in a lab meeting and we've been using a drug called Anakinra to treat COVID patients. This was a few years ago when we were trying to figure out what to give patients because we had no idea how to turn the inflammation off. So we gave Anakinra and we saw the exact same effects and this is a drug that's already FDA approved and used for a variety of obscure conditions you only learn about in medical school. Uh But we knew that it was available and uh it was exciting because we also saw recapitulation of the anti tumor effect in uh multiple other tumor models. So this is a Ortho topic model of colon cancer and Ortho topic model of pancreatic cancer, which is extremely resistant to immunotherapy. And specifically, if you focus on these old mice, it sort of silly that we're studying cancer in young mice because nine year olds don't get pancreatic or lung cancer. Thankfully. So, here we're looking at older mice and who have very different immune systems. And here by giving an Aina, we can significantly decrease the growth potential of all these different solid tumors. So it seems like maybe we shouldn't just be blocking IL four, but we could also potentially be blocking these other uh mitigators of inflammation. So now uh we, we just started enrolling to this clinical trial um where we're adding on Anakinra to what we were doing before. So this is just giving you an idea of this concept of a bench to bedside to bench bench approach is we really want to rapidly translate our findings in the laboratory into patients, but also be learning from patients constantly bringing back uh their samples and, and learning from them. And that's something actually very unique at Mount Sinai that we're able to do. So. Uh in summary, you know, this is where we started about 10 years ago, just giving patients chemo and unfortunately, everyone was dying. Uh We added on PD one blockade and it's a significant improvement, but unfortunately not enough. And so our work is really, you know, trying to identify these novel immunotherapy combos. But while we're doing that, uh we're also studying these samples. So that we can better identify biomarkers because not everyone's gonna need do pillow A, some people might need drug X or drug Y and only by, you know, identifying biomarkers that really tell us what way did this patient's immune system get hijacked by the tumor. Can we figure out how to really un hijack that in a much more personalized way, uh, than we, than we can do by just developing a drug for everyone. Because unfortunately, you know, there's, there's no silver bullets on oncology. And obviously, our goal is eventually to get to the point where we're curing all of our cancer. And uh everyone else's death is uh up to the rest of you guys in medicine to fix. So, uh so thanks first and foremost, uh to our patients and our families who are in their families who spend way too much time with us. It feels like my family. Um This is just a small sampling of the team, the, the, the trials that I'm talking to you about really take hundreds of people um uh uh between our nurses and our research coordinators and all the physicians and scientists in their labs to run these trials. It's really um uh a team effort and, and Miri Mora is really my partner in crime and an amazing collaborator. And, and finally, um I just wanted to say a word of thanks to all the inspiring physician scientists. I've been here for 20 years and I think Sinai really is the ultimate place for physician scientists. And I was blessed to be uh mentored and trained by uh two of the Bath Lloyd mayor uh was the former chief of G I and he was one of my uh co phd mentors. Um And, and really taught me what it means to be a physician scientist alongside Charlotte Cunningham Rundles um and Barbara Murphy, uh she introduced me to my first patient um uh after my white coat ceremony as a first year medical student in 2005. Uh and she was always a, a mentor and an inspiration. Uh not only on how to be a physician scientist, but she was also a beautiful human being. So thank you. I have some questions. Um Beautiful lecture. Um You mentioned a little bit about biomarker. So do you have any idea whether um like the levels of these cytokines have any response to people? So that's the holy grail. So we, we, we actually have about a third of patients. So we finished the first trial and it was 21 patients and a third of them actually achieved stability or response, which was amazing because we're just giving them allergy medicine, but we need to identify what is the, the marker there. And we, we're looking in the blood for some sort of type two signature. Um The, the issue is that il four is actually at very low levels in the blood So we're doing some high resolution, we, we did a link on the patients, but now we're doing a more high resolution luminex to try to um see if we can uh really see a signature of the, the uh type two cytokines. But I think the other issue is that you don't see a lot of these type two cytokines in the blood or in the tumor. It's really within the, the bone marrow that you're seeing most of them made. And so we're looking in the, in the blood, but it's really, you know, sort of peeking through a hole and trying to see if we can figure out what's going on in the bone marrow. But we're, we're doing pretty exhaustive analysis of the blood right now. We're, we're looking at the tissue also, but obviously, we ideally have a blood, uh based biomarker that would help us, you know, figure out which patients should get with drugs. There's at least one, from Doctor Gallagher. Um Great talk Tom. Have you seen any adverse effects in people you gave to pili and anti PD one treatment to, would you expect fewer adverse effects? That, that's a great question. We actually are, are working with some of our dermatologists because we're actually treating immunotherapy related dermatitis, which is the most common immunotherapy related adverse event with Dupilumab. Um, and, and they, in, in Durham, they give duy to everyone. It seems like we should put it in the water. Um, but they actually are having very nice responses. We're, we're not clear if that is, is helping also with cancer outcomes in those patients. Um, but so far we haven't seen any, uh, side effects with the DP. Yeah, I love to talk. Thank you. Uh, you gave David nightmares when you spoke about the concept that you're circulating cancer mutations and, and everything. That's a theory. I don't know. But can you, for us, what would distinguished individual who goes on to develop cancer? Given that process may be ubiquitous versus an individual who doesn't go on to develop cancer? What's different about the response? That's primary? Yeah. No, I mean, I think that this really goes to the fact that I always tell patients when they come see me that, you know, everyone in the waiting room has a radically different cancer and a radically different immune system and a radically different, you know, line sequencing and um all of our immune systems are different. I think that the, the theory, unfortunately, we are seeing more and more cancer in younger patients. I keep on getting 30 year olds referred to my program and it's giving me nightmares. Um But the, the theory and, and this is the, the I highly recommend you guys check out the science paper last week. It's a potentially transformative paper because what we're seeing is that um we, we saw it in mice, but then we started looking at humans. And we see this very strong correlation with age with this development of sort of basal emergency myelosis or aberrant myelosis pathogenic myelosis. So you see more and more you basically see this skewing in the bone marrow towards myeloid precursors in a way from lymphoid precursors similar to the NLR which is, you know, one of the most basic ways in which we can prognosticate how patients will do in cancer, the neutrophil lymphocyte ratio. But um we, we see more and more of this sort of aberrant myelosis as people get older. And the theory is that, that sets you up not only for overly exuberant responses to things like COVID. So it might explain why the 80 year olds were dying and the 20 year olds weren't. Um but it also really sets our body up to be receptive to these cancers. So instead of our T cells saying, hey, that doesn't belong here and killing it, you might all of a sudden reach that threshold where not only is your immune system dysfunctional enough, but you have a cancer cell that got just enough mutations and KRS and P 53 and everything else to, to sort of pass the finish line and allow it to grow and, and you know, once it starts growing, that myelosis, that emergency myelosis then sort of enables it to grow even more. So it really creates this fertile soil for it to grow it. Um Well, next question uh, what is the situation with common cancers such as prostate cancer that do not seem as responsive to immunotherapy? Yeah, that's a, that's a Nobel prize waiting to be won. Um, uh, we don't know. Um, they do have mutations, they have lots of immune cells, lots of macrophages. So, and, and there's lots of T cells in there. Um, one of the thoughts with pancreatic cancer is, it really has a very, um, uh it, it has a slightly different immunosuppressive phenotype. There's lots of stroma, it's kind of a cancer that builds a wall around itself and protects itself from your immune system, you know, recognizing and attacking it. But uh there's lots of barriers there. We do have um some exciting new agents in, in our unit where we're actually seeing immunotherapy work in pancreatic cancer for the first time, which has really never been seen before. Um And so I think that we are making progress, but it's definitely uh it's, it's one of the toughest cancers because not only does it usually present at a much more advanced stage and patients immediately have, you know, medical complications. Um But it also has its own sort of collection of immunosuppressive mechanisms and we probably have to, you know, specifically target that in the case of pancreatic cancer. We have one more question from another question and this one from Doctor Kraft, wonderful talk as someone who uses anti type two biologics frequently. Do you see an increase in asthma in your patients. There is an increased risk of malignancy and allergic diseases. So, perhaps we are reducing that risk by using these biologics for their allergic disease. And then have you thought about using anti IO five treatment for your patients? Given the direct effect on Eoin ofilia? That, that's a great question. Eosinophilia. I'll take that one first. Eosinophilia is a little complicated because it seems like, you know, type two, it is a type two granulocyte. We see eosinophils in the tumor and in the blood, we see an eosinophilia very commonly. And the data there actually sometimes patients with the eosinophilia actually do better with response to checkpoint block A. We have no idea why we don't understand the mechanism there. Um But it is, you know, it is a type two cytokine. It, it definitely could promote a more, you know, uh permissive environment for cancers. And so it would make sense to explore ill five and there's some other like IL 33 TSL, the other type two cytokines that are interesting. Um As far as uh DP, we were just uh talking to cap is all of a sudden Dilma is now FDA approved for COPD patients. COPD patients are typically smokers. These are patients who should be in our lung cancer screening program. And so we're hopeful and we're gonna be able to see this sort of in a real world clinical trial by starting these patients on Dilma and there's only a subset of patients with Eina that are gonna be able to get it, I think. Um but it, by starting them on D pili, hopefully we'll actually see uh less cancer in those patients. And so I don't think that we've been using dab enough to really argue that this is AAA cancer preventative medicine, you know, it's only been around for 10 years or so. Um But it will be interesting to see how uh disrupting the IL four access, you know, might have long term sequela in, in, in decreasing the the incidence of cancer. OK. I can talk for collaboration on the care of our patient. Um You mentioned that those who get the related adverse Andy tend to have a better progress from the cancer side. But I was wondering um grade three or grade four related avery. Uh what what kind of response rate you see in steroids? Um kind of a kitchen that possible. Yeah, it's tough because, you know, when we get to most of the grade 34 adverse events, we actually are able to control with immunosuppressants. And so it's not uncommon for us to cause pneumonitis, colitis hepatitis and usually we're able to get it under control with rapid treatment. Um but we do have patients um that you guys end up taking care of for very long periods that do not uh respond, you know, despite uh high dose steroids, you know, we're giving post do steroids, TNF blockade, il six blockade and, and we still are not able to, to bring in the inflammation. And a lot of the times that's because the inflammation has already caused so much damage that I it's, it's a, it's a foregone conclusion, the way that things will go. So we, I'd say the majority of the time we are able to control um uh very se serious adverse events, even things like, you know, grade four colitis, grade four hepatitis. Um, and, and it's not a guarantee, you know, I always, I, I, like I said, it's sort of a silver line that there's a trend towards better responses and it's a, it's a significant trend. Um, but you still have patients that develop irees that don't do well and you have patients that have no toxicity, which are the majority of our patients that get cured of their cancer. And so it's, you know, you, you can't really, that's the tough thing is you can't really tell people, I know our patient really wants statistics and says, you know, tell me exactly what percentage likelihood this is gonna happen. We can't do that because everyone in front of us is not a 45% you're either a zero or 100. Um, when it comes to, uh, you know, cure and response to therapy, it's tough and it's also tough just because it's, you know, these things are so rare and they present in such a motley crew way and, and a lot of the times they'll end up going to a community hospital. So they only get transferred after a week of care that it's very difficult to run clinical trials in this. It's impossible to run clinical trials in the space really. And so we're, we're just always trying and we have a effort going on in the lab where we're trying to get blood and uh biopsies from patients getting colitis. So we can just better understand their trajectory and how we should best intervene because we give TNF blockade because they have colitis and we give TNF blockade for ulcerative colitis. So that's why like, you know, i it basically is just sort of deduced from that, but they are radically different mechanisms of action. So we really need to better understand these IR AES and study them more so we can better treat them great. Well, Tom, it's great to see the amazing research that you're doing. So. Congratulations. And thank you so much.
