All right, good morning. You guys are troopers being here Wednesday morning, 8 a.m., the last day of the conference. Thank you. Thank you for being here. My name's Christine Argento. We have this amazing panel of physicians, and we're talking today about a really exciting and interesting topic that's really new and innovative. So talking about intratumoral injections. And so I would like to invite, without further ado, Dr. DeMaio, who is currently an assistant professor at NYU. Thank you, Christine, and again, thank you guys all for coming here early on the last day of the conference. But I'm happy to be part of this session, which has some true experts in the field, so I'm excited to learn with you guys as well about intratumoral therapies for lung cancer. And my brief talk will kind of give an overview, and then we can lead into some of the more specific topics. So no disclosures financially related to this presentation. Some of the topics discussed may include both research and off-label uses of devices or medications. Again, big-picture objectives, just to talk about intratumoral injection, how it has been used and how it can potentially be used in lung cancer. So always good to know the history behind, you know, medicine and learning about how we got to where we are today. So the first thing I want to point out is Dr. William Coley. Do any of you guys know about this story? A couple heads here. So William Coley is known as the grandfather of immunotherapy, and he noticed back in 1891 that patients who had cancers, but specifically sarcomas, had some spontaneous regressions of these cancers when they developed erysipelas, or skin infections, over these cancers. And then his career, he actually injected these, what he ended up being called Coley's toxins, but basically cultures of live bacteria into these tumors, and again, noted in many cases, significant regressions of cancers. Obviously the kind of immune system was not really known about at that time, but again, in retrospect, it's just pretty impressive what he was able to demonstrate. And here, this is actually the, you know, the title page of his paper, and this is actually the first tumor that he injected, and there's a reaction to the injection of streptococcus bacteria, which I thought was pretty cool. With the development of chemotherapy and radiotherapy, a lot of the work with injection was kind of left by the wayside, because these were new, great techniques to treat cancer. And in the 1950s, specifically, there was experimentation about different administration techniques, and there was, you know, anything you could ask of, right? So intravenous, intratumoral, you know, intrathecal, everything they, you know, could possibly ask was tested, and here, again, one of the early papers, this just shows administration of chemotherapy. This is intraarterial, but again, if you notice, this is the common carotid artery. So again, some of these early studies, people were injecting chemotherapy into the carotid artery. So it just, again, gives you an incidence of the scale and how this kind of thought came about. There were local responses to intralocal chemotherapy, but ultimately, nothing was durable. So this was not really too much further experimented with. In the 1970s, BCG was used as a local immunotherapy, first in melanoma, just because these skin lesions are accessible, but then also in lung cancer. So this actually is a picture of a percutaneous injection of lung cancer with BCG, and this is the response that was measured afterwards, and this was noted as a granulomatous response to the BCG administration. Again, in the big picture of things, BCG is also a standard therapy for bladder cancer, non-myoinvasive bladder cancer. So there is precedent for using local therapies for treatment of cancers. The story continues with the development of more bronchoscopic procedures and better techniques and tools. Different medications, let's say, were injected into tumors, and here, again, you have a picture of a bronchoscope where a needle was used to inject a tumor with a cytotoxic agent just to relieve, really, airway obstruction, hemoptysis, for palliative purposes. Again, further experience with bronchoscopic delivery, intratumoral chemotherapy, including, again, lots of different agents, cisplatin, paclitaxel, anything you could really ask of, was injected into, again, central airway tumors, mainly for palliation. And again, here you can see first forceps were used to debride the central airway obstruction, but then chemotherapy was injected around the airways to access deeper lesions, in theory, could prolong response and maintain patency of the airways. In the 2000s, gene therapies were being experimented with in many diseases, but also lung cancer, and gene therapy was administered bronchoscopically, percutaneously, through various routes. Here are a few of the pictures from the early studies that looked at responses to gene therapy in lung cancer. Over the next 10, 15 years, again, more development of tools, techniques, two that I'll just point out quickly. So number one, on the left, we have an EBUS scope, and this has really developed the field of interventional pulmonary, but has also been, because of the diagnostic capabilities, but also has therapeutic capabilities as well. And specifically because you're able to visualize the lymph node, the tumor, whatever you're doing, and inject the needle under direct visualization, I think there's definitely potential there. It has been used to inject central lesions, for example, in patients who are not candidates for radiotherapy. So that was one kind of technique that I just wanted to highlight. The other, obviously, is getting a lot of press is robotic bronchoscopy, and this really has extended our reach to the periphery, and now can we use a bronchoscope to inject peripheral lung lesions that typically were outside of the reach. Obviously, we'll talk more about that with Dr. Argento shortly. The last thing I want to highlight here is TVEC, which is the first FDA-approved intratumoral therapy. Now, this is not approved for lung cancer. This is approved for melanoma. But it's essentially a modified virus that can help with stimulating the immune system. So that's kind of background. Where are we today? Why should we use local therapies? And I'm just going to quickly point out some of the reasons why it could be helpful. I've listed three kind of general categories of systemic therapy based on kind of a recent review paper. Systemic therapy, this is what we typically give in cancer, just intravenous administration, and it distributes throughout the body based on its pharmacokinetics, et cetera. Easy to give. Problem is toxicity. And specifically, with immunotherapies, immune-related adverse events are not uncommon, and sometimes they can be life-threatening. So one of the major benefits that we're hoping for with intratumoral therapy is increased safety. One comment about tumor-targeted therapies, this concept is you can give a drug systemically, but maybe it is bound to an antibody or something that is concentrated in the tumor environment. So it's not delivered locally, but it can concentrate locally in the tumor. And again, intratumoral therapy, directly accessing a tumor with local injection. And again, I think the combination immunotherapy potential is one of the reasons why this could be great. In order to understand why we would want to do this, it's also important to understand the microenvironment of the tumor. I'm just going to point out a few examples here that have been described. So here is the tumor. And cytotoxic T cells, these are these yellow cells here, in this tumor are not able to infiltrate this tumor because of the tumor itself, because of some of this fibrotic nest around it. And because of that, the immune system is not able to eliminate this tumor. Now, there are other tumors that have an inflamed microenvironment. In this case, you have cytotoxic T cells infiltrating the tumor itself. You have high PD-L1 expression. And this is ideal from a systemic standpoint in terms of treatment with some of the immunotherapies that we use nowadays, including checkpoint inhibitors. So this is another environment that has recently been kind of described. But there are other microenvironments. For example, tertiary lymphoid structures also may be involved in the formation of immune response. And it's basically a structure similar to a lymph node. I don't want to get into all the details here. But the point is that these are all signs of the immune response to the tumor. And one of the big concepts is, can we take a tumor where the cytotoxic T cells are not able to infiltrate it and create an immune response and convert it into a high PD-L1 expressing tumor that actually responds well to systemic therapy? So can local therapy do that? One other point that I want to make is that tumor environmental factors also affect drug distribution. So tumor size, tumor heterogeneity, a lot of times you get necrosis in parts of a tumor, excuse me. There's a lot of variables that affect how a drug can distribute through a tumor. So that's also just big picture, something that we have to incorporate as we're talking about injecting tumors, whether it's bronchoscopically or percutaneously. Here I have just highlighted, again, the goal of this local therapy is that we are taking a tumor that's not responding to immunotherapies and making it respond to systemic immunotherapies. And here are a few different ways that have been suggested that it may work. This is the cancer immune cycle proposed by Chan and Melman in 2013. But again, all of these different steps of release of cancer cell antigens, for example, can be promoted by injecting a tumor locally with an oncolytic virus. And then in theory, if there's systemic treatment as well, there could be synergism between these therapies. And again, I'll let the details of that be touched on by some others. Again, many classes of intratumoral therapies are being investigated. This is just a hierarchy here. I'll just highlight a couple. MRT cells, again, could potentially be beneficial to be treated locally. Oncolytic molecules, including those that induce immunogenic cell death, ICD. Pathogens, bacteria, specifically I highlighted this just because of the story about William Coley that I just told you guys, is these can be used as therapies. And then immune checkpoint monoclonal antibodies. Could these be administered locally and have more effect? A few potential indications. So number one is local treatment of lesions that aren't otherwise able to really be treated well. So I kind of mentioned the recurrent non-small cell lung cancer in a previously irradiated field is kind of one example where there's not really a good therapy for that at this point. So using this as a potential treatment strategy, a local treatment strategy in that point. A combination approach for malignant area obstruction, perhaps to prolong duration of response. And then as we get down here, these are a little bit more investigational, but certain immunotherapies may require or be more effective with local delivery. So diagnostic viruses, cell-based immunotherapies, for example. And then could neoadjuvant treatments delivered at the time of diagnostic bronchoscopy potentially initiate a systemic immune response, potentially treat tumor-draining lymph nodes? I don't know, but these are all just questions that kind of have been posed in the field. A couple of administration techniques. Again, I'll kind of just point out bronchoscopic can be used both by robot or otherwise standard measures, eBus, TBNI, and then percutaneous techniques. I'm going to just leave that there just because I'm going to let Dr. Argento and Sheth talk about that. And then these are just some of the ongoing studies. This is not a comprehensive list, but these are some of the studies I found on clinicaltrials.gov. A few things just to point out. So there's studies looking at intratumoral therapies for early-stage cancer in a neoadjuvant fashion. There's intratumoral studies looking at therapy for advanced-stage lung cancer. There's, again, this is using oncolytic virus. This is a study actually combining intratumoral therapy with radiotherapy and actually injection of a radio enhancer. And then, again, administration techniques. Some studies allow for both bronchoscopic and percutaneous delivery. Some require one or the other. But again, I think we have the ability now with all the tools to reach pretty much any lesion that we need to in the lung. So that is kind of all I have in terms of the overview. Thank you guys for your attention, and I look forward to hearing the others chat. Thank you. I feel like I learned from that. That was amazing. All right, so as I mentioned, my name is Christine Argento. I'm really excited to be here. Thank you, Dr. DeMeo, for inviting me. We're gonna talk a little bit about bronchoscopic approaches to intratumoral therapies. I do consult for a few companies. None of them will have any relation to the contents of this talk. So I think Drew actually did a much better job with his timeline than I did with mine. But I just wanted to point out a few things that he definitely mentioned, sort of the advent of new technologies. And I think that's really what's pushing this field forward. We're now able to reliably and with visual guidance inject into tumors using EBUS. You can still use a traditional needle, but I think most of us would go ahead using EBUS. We're able to identify the vascular structures and the vascular areas within lymph nodes and tumors in order to avoid injecting into those areas and inject into more sort of the meatier areas of the lymph nodes. And now with, I think, navigational and robotic platforms, we are reliably able to get to peripheral tumors in the lungs. And unlike ablative therapies, where you have to be sure to completely ablate the tumor, injecting with different therapy and different therapeutic agents is something that I think is feasible to start now that we're able to reliably reach these lesions. And so for me, I sort of split bronchoscopic intertumoral injections into two basic forms. So there's sort of endobronchial therapy and then there's transbronchial or transtracheal therapies and injections. And so just, you know, for myself, had to think about why are we doing this anyway? So the big why. What are the benefits of intratumoral injections over systemic drug administration? And really you wanna concentrate your therapy within the tumor. And there are studies that show that the concentration significantly is improved over systemic administration of drugs. So it can be up to 10 to 30 times higher intratumorally if you inject it locally rather than giving it systemically. You end up also with low systemic concentration. So most of these studies actually do PK values in the blood and find that there is not a huge systemic absorption after intratumoral injection of these therapies. Also the drugs may actually stay at therapeutic concentrations longer than if you gave them systemically. So they're not being processed and eliminated through the body. They're being sort of depo-formed at the area that you're interested in. And so they may actually stay at therapeutic concentrations much longer than you would have if you gave them systemically. And then with different preparations like liposomal or microsphere drug formulations, that can even extend the therapeutic timeframe even longer. You can also deliver these really precisely, so exactly where you wanna put them. And ideally if you give a drug locally, especially if you're giving it into a tumor or into a lymph node, ideally it's gonna drain similar to everything else. And so you'll end up with some drug following the local lymphatic drainage, which may or may not, we don't really know yet, but it may treat micrometastasis. And so again, all of these I think are really important things to consider. And so talking about sort of that first endobronchial administration of therapies. So this was a multicenter phase one trial that was published in 2019 in CHEST. And it looked at patients with stages one through four, non-small cell lung cancers. They looked at 19 patients who had malignant airway obstruction. These patients underwent debulking with multimodality therapies. And then they ended up injecting with Paclitaxel using a blowfish catheter. And I'll show you what that looks like. And multiple injections were performed and I'll kind of talk about that. So this is what the blowfish catheter looks like. It's pretty interesting design. So it's a catheter at the end of it. It's got a balloon. And within that balloon, there's a microneedle. And so as you inflate the balloon, the microneedle will then stand on end. So you can kind of see it. I don't know if you can see my pointer. Here we go. So you can see it's sort of embedded within the balloon here. As you start inflating the balloon, the needle is now sticking up. And as the balloon gets fully inflated, it's gonna stick through into the airway mucosa. And so you can deliver a drug there. And it's a 34-gauge needle, so extremely small caliber. And what you can do then is you can administer part of the drug into the mucosa, into the submucosa. And then you end up turning the catheter. So you would do multiple injections into the same area, as many as you would need. So you can inject at 12 o'clock, three o'clock, six o'clock, nine o'clock, for example, if you had something that's circumferential, or you could target where you needed it. And this is one of the examples of the patient response. So you see on the picture, the baseline photo A, shows that you have right main stem mass. They locally debulked it using rigid bronchoscopy and other instruments, and then treated it with Paclitaxel, and ended up six weeks later going back in, and you see that the airway is actually patent. There were no adverse events or severe adverse events. There's much less stenosis post-procedure versus pre-procedure, and they found that no patient required any further airway interventions or stenting after treatment. So that was pretty interesting. Often we see also with airway obstruction that we're not just gonna wanna do a local injection, but often we're doing sort of trans-bronchial or trans-tracheal injections. So we see about a third of lung cancers that are complicated by malignant airway obstruction, and they are mostly symptomatic, and generally require urgent recanalization of the airways. So we often do debulking procedures, but I'm sure most of you know, these things tend to be pretty time-limited, and so you have to go back and re-debulk at several intervals. And so it's effective, but the improvement is typically short-lived. And so now we wanna start thinking about, again, sort of extending the therapeutic intervention that you've just done. And you wanna think about things that Dr. DiMaio mentioned, so the tumor vascularity, the size, and then things like density as well of your tumor, and how well your drug is actually going to go through the tumor environment and be able to have an impact. So most of the studies that are out there actually look at cisplatin. So this was a study published back in 2015 looking at 22 patients who were treated at a concentration of one milligram per ml of cisplatin, injected directly into the tumor. They used a maximum dose of 40 milligrams. Each site received anywhere from one to four injections, so they tried to just space it out, and then they got weekly dosings for up to four sessions. And what they wanted to look at as a primary endpoint was the reduction in airway obstruction, which was just a visual assessment. And the patients were then divided into two groups, the responders, if you had more than 50% reduction in your airway obstruction, and non-responders, if you had less than that. And what they found was that 71.5% of patients ended up having more than 50% reduction in airway obstruction. And so you can see that here. That also corresponded with survival and progression-free survival for these patients. And not just original tumors, but also recurrence. After patients have already had radiation therapy at targeted sites, their treatment options after those interventions tend to be fairly limited. So they can have palliative radiation, sometimes chemotherapy or best supportive care, which seems less than ideal. So they took 35 patients and injected 50 sites, again, with cisplatin. And they found that 69% of these patients had complete or partial response, and so these were considered responders. And only 31% had stable or progressive disease and were labeled non-responders. And so again, they got the same 40 milligrams as a maximal dose of cisplatin, one to four punctures per session for a total dose of 40 milligrams. And again, these are the survival and progression-free survival. Again, you see that the survivor, or the responders, did much better overall than the non-responders. Going back to something in Dr. DiMeo's timeline was the ethanol injection, and that's also still being looked at. So ethanol's been really pretty extensively used as a sclerosing agent for interventional therapies for a multitude of things. And it can be used, again, as an adjunct for after debulking in the airways. It tends to cause necrosis in pseudomembranes. So this was a retrospective study between 2015 and 2020, where 42 patients underwent intratumoral alcohol injection, and they found that 81% had about two bronchoscopies that were needed in order to evaluate a response, but most had a good response, with airway patency improved, again, over 50%. And they used 98% dehydrated alcohol. They really tended to use this. It was considered if the patient had particularly bulky disease, extensive mucosal infiltration, or if bleeding precluded further tumor debulking. So this was really used as an adjunct to our typical rigid bronchoscopy with debulking. And these were their results. So you see on the picture on the left, image A, you see complete obstruction of the right main stem bronchus. In B, you see after the tumor had been injected, you see the pseudomembrane formation. And then C was six weeks later, you see that there's actual airway clearance and patency of that airway. And then people are starting now to use combinations of things. So again, cisplatin is pretty commonly used, and now they're using it with endostatins for intratumoral injections. This was a small study published earlier this year looking at 10 patients, again, undergoing bronchoscopic tumor, debulking, and followed by intratumoral injection with systemic therapies as well. And you can see the chest CTs sort of before and the bronchoscopy before, which is all on the top line. And then one month after treatment, you can see that the airway obstruction is almost completely cleared. And then currently, I'm participating in what's called NanoPak trial, which is a nanoparticle formulation of Paclitaxel. It's a phase, they call it a phase two, it's probably a phase one to two trial. Currently ongoing, we're enrolling 18 patients. It's a multi-center trial for patients who have advanced stage lung cancers that are not surgical candidates. But it can be small cell or non-small cell. And we're gonna use EBIS transbronchial needle injection. They get four injections, four weeks apart, and then repeat CT scans, PK samples, histologies, et cetera. And it will be interesting, so kind of heads up, keep looking for this trial to see. And I think it sort of highlights sort of how people are thinking about these drugs now. So do we give single injections? Do we give multiple injections? What's the ideal time between them? We know that the concentration of therapy definitely is improved when you're administering your drug locally. But how long that effect lasts and whatnot, we're still evaluating. So lots to come. And so I think for future directions, we're really looking at intratumoral and intranodal immunotherapy. It will be fascinating to see what those outcomes look like, using novel tools and methods of delivery and different formulations of the different tumor therapies. And so I'll leave you with a few words of wisdom from Chevalier Jackson. So educate your eye and your fingers. Be sure you are right, but not too sure. Follow your judgment, never your impulse. Cry over spilled milk enough to memorize how you spilled it. Let your mistakes worry you enough to prevent repetition. And just remember, nature helps, but she is no more interested in the survival of your patient than in the survival of the attacking pathogenic bacteria or tumor. So with that, I'm going to end. And I would like to welcome Dr. Sheff to the stage. He is joining us as an interventional radiologist and associate professor of medicine at MD Anderson. And we are really fortunate to have him here. So thank you so much for being here. And I'll just open your talk. Great. Thank you so much for the introduction. And thanks so much for having me, guys. Like Dr. Argento said, my name is Rahul Sheff. I'm an interventional radiologist at MD Anderson. So it really is a pleasure and privilege for me to talk to you guys about a topic that's very near and dear to my heart, which is this field of intratumoral immunotherapy. These are my disclosures. A couple of these are intratumoral immunotherapy companies that we're doing trials with. So Dr. Domingo gave you a great overview of this field of intratumoral immunotherapy, so I won't spend too much time on that. My real goal here is to share with you all my perspective on this field kind of across the spectrum of oncology because that's the sort of trials that we do in IR. And also share with you the lessons that we've learned from doing these procedures and how I think we can do them better. And ultimately, I hope to kind of excite you guys from an interventionalist perspective about how critical it is that you guys play a key role in designing and executing these studies. So like Dr. Domingo said, there's a huge range of types of injections that we're doing, spanning from biologic devices and drugs to bacteria, small molecules. But the concept is the same. As we know, systemic immunotherapy has really revolutionized cancer care. And for some patients, it leads to really durable, sustained responses. But unfortunately, for the majority of patients, they actually don't have any objective response. So what we know is that when patients have a smoldering immune response to the tumor, that when you give them the systemic immunotherapies, they're gonna respond appropriately. But for a lot of patients who have these so-called cold tumors, the immunotherapy is not gonna be of any benefit because there's nothing to activate. It's just, you know, it's quiescent. So what if we do something to that tumor microenvironment to kickstart the immune system so that when you add on the systemic checkpoints, you can actually set the chain reaction going? And so that's the whole concept of this field is that let's deliver something right into the heart of the tumor to fire up the immune system so that you can create local immune education and then with the checkpoints on board, you can have that immune response spread throughout the body and generate what we call this abscopal effect, which is really where the magic happens, where you can intervene on one tumor in the lung and now all the tumors throughout the body melt away. Sounds like magic, but as you'll see, it's actually something that we can see on a daily basis nowadays. So this is our experience at MD Anderson. This is a study that we published a couple years ago now that summarized our first 500 patients on some of these intratumoral immunotherapy trials. By now, we've done about 2000 of these procedures. As you can see, it spans the whole spectrum of oncology in terms of the types of cancers that we're treating. The most common certainly is a melanoma. Like Dr. DeMaio said, there's one intratumoral immunotherapy that's approved clinically, which is TBEC, and that's for melanoma. So no surprise that that's the most common malignancy and no surprise that the most common site we're injecting are these subcutaneous melanoma lesions. But you can see we're injecting kind of from head to toe. We're mostly doing these with ultrasound for superficial ones, but certainly have plenty of CT guided experience for this. And as you'll see in panel C, there's a large diversity in the types of needles that we're using, and we'll talk much more about that later on in this presentation about how we do these procedures. And so the perspective I wanna share with you right now is where the field is across the board. So there was a lot of excitement in a lot of phase one trials about three or four years ago, which is where the bulk of our experience grew from. And some of these studies in the phase one and phase two, which we conducted at MD Anderson, really spectacular data where you saw these abscohaloxane tumors melting away after just injecting one small nodule. I'll highlight this Illuminate study, which was a trial that we did at Anderson for phase one and phase two. And so I got to know pretty much all of those patients on that study. And you really did see remarkable effects. Unfortunately, when it expanded to phase three across multiple centers, it failed. And likewise, there was a study, Keynote034, which was combining TVEC, which is approved for single-agent melanoma with a P1 inhibitor, again, with the hope of generating the subscopal effect. And that unfortunately failed as well. These two negative studies came out in the past six to 12 months. And so it's been a time of circumspection for the field to sit back and think about, well, the concept is sound, the biology seems to make sense, but why aren't we seeing these subscopal effects in our larger phase three studies? And my feeling and sort of the sentiment that I expressed to oncologists is that your therapies are great, the concept is great, but it's failing not because we got the biology wrong, but because we got the delivery wrong. And that's really what I wanna focus and share with you guys what I mean by that, because that's where we come in as interventionalists how to get the delivery part right. So we do several studies where you can actually see where the drug ends up. And so that's been really enlightening for us to understand how effective we are with our approaches. So these are liver tumors, and sometimes it goes really well and you stick a needle into it and you inject the drug, which is this high-density material here, and it fills the tumor up like a big balloon. So these are a couple of lesions, you inject it, the whole thing's filled with the tumor, you know it's gonna respond and have a good outcome. Sometimes it's bad like this, where here's the tumor here, you can see the drug leaking out the needle tract from where we entered it, and also kind of spilling half in, half out, same sort of story here, leaking along the needle track. And then it's like really ugly sometimes where pretty much all of the drug is outside the tumor. So this little meniscus is on the outer margin of the tumor, which is this hypotenuating lesion right there. Likewise here, this is a big three centimeter tumor, so no question that we got the needle in the right spot, but all the drug has spilled out outside the tumor. And I wish I could say it's only for liver lesions, but unfortunately we see the same thing for lung tumors too. So here, again, showing we can get a needle right into the heart of the tumor, that's not the hard part. And in this case, we had plenty of room posteriorly for the injection to ideally kind of localize in the tumor, but unfortunately all the drug leaked out of the back end and there was pretty much nothing inside the tumor. Likewise here, this is a post-radiation recurrence that we were injecting and with the green circle highlighting where we wanted it to go, you can see almost none of it ended up there. Didn't hit the aorta, yes, all right, score one for us. That's right. And again, same thing here. So tumor here, drug everywhere but the tumor. So what's the implication of that? You know, of course, if the drug doesn't go where it's supposed to go, it's not gonna do what it's supposed to do. But almost just as importantly, if it ends up where it's not supposed to end up, it's gonna do what it's not supposed to do, which is what I mean by toxicity. So in our review of these 500 patients, and of course, these are all different drugs and with a wide range of mechanism of action, but at the end of the day, these are very potent immunotherapies. The reason we're giving them intratumorally is because they're not safe for systemic delivery. So when they leak into the blood vessel and get systemic delivery, you start to see toxicities sometimes while they're even on the table. So you'll get rigors and chills and hypotension and the whole sort of SIRS thing within a matter of minutes of your procedure. And so the complication rate isn't trivial. It's not terribly high, but it's not trivial. And it's something that, you know, as interventionalists, we need to be aware of. So what's going on here? Why are we so ineffective in delivering these drugs? So we, you know, we think a lot about the biological barriers to therapy, but these physical barriers are almost as important, certainly from our perspective, for the delivery standpoint, more important. So these are things like solid stress, interstitial fluid pressure, and irregular microarchitecture, and sort of tumor stiffness. That's all of these things conspire to prevent our drug from going where we want it to go. So this is my very simplistic kind of breakdown of what I think is going on and what we can do to improve it. So there's three variables I think that we can modify to improve our delivery. One is, of course, the injection technique, so how we're delivering the drug. The second is drug formulation itself, so what we're delivering. And the third is the tumor microenvironment, so where we're delivering. So for injection technique, can we think of different needle designs, different injection rates, to improve the localization for the drug formulation? You know, nanoparticles, hydrogels, we've got a whole biomaterials revolution going on right now, can we take advantage of that? And then the tumor microenvironment, you know, we talk about cold and hot tumors from an immune standpoint, but should we also be talking about hard and soft tumors? And can we think about ways to make hard tumors soft so they're more susceptible for local delivery of these drugs? And, you know, this is just to show that there's plenty of devices that are out there on the market and on our shelves that can improve delivery. So for us, you know, we almost always use these just straight-up end-hole percutaneous needles for our percutaneous procedures. But there's other stuff that's out there that is much better designed for local delivery, and we've seen that in a quantitative way in our preclinical studies, that changes in your needle design lead to substantial improvements in local delivery. And likewise, for some of the procedures we do that are transarterial, we, again, just use a usual end-hole microcatheter most commonly, but we have other options that are on the shelf that can definitely improve our local delivery. And so, you know, for any proceduralist, it's very straightforward. The outcome of any procedure is contingent on the technique that you use. So better technique leads to better outcomes, and that's really what we're trying to emphasize here. So in summary, these trials are complicated. There's a lot of moving parts, and it's important for us to get involved early. They're often designed by pharma companies who completely ignore the delivery side of things, and that's really where I think we add a lot of value. We can do these safely both for superficial lesions as well as deep lesions, and if some companies are reluctant to do that, you can just reassure them that it's safe. We need to be familiar with are the acute immune-related adverse events that can happen literally on the table while we're doing these and how you would manage it. And then ultimately, the outcomes are dependent on the technique itself, and so we need to be thinking deeply about these delivery techniques and standardizing and using evidence-based practices to optimize our delivery. So thank you very much, and I'll be around afterwards to talk or answer any questions. Thanks. Wow, thank you. That was amazing. I wish we had that many tools for delivery. We have like one tool. That was incredible. Well, it is my great honor to introduce Dr. Sturman, who needs really no introduction, a professor of medicine at NYU, an amazing friend, mentor, and colleague. So I'll start your talk. Thanks so much, Christine, and thank you all for being here on Wednesday. And you're all incredibly hard acts to follow, especially with all the cool tools that my colleague from MD Anderson showed, so we're insanely jealous. But I'm Dan Sturman. I'm up from NYU, and I'm gonna be talking a little bit about how we combine local and systemic therapies in a precision medicine fashion to help our patients. So these are my disclosures. The most relevant disclosure is I'm gonna be talking about a clinical trial, which is the LUTKO2 clinical trial, sponsored by a company named Kandel Therapeutics. I have no financial arrangements with this company and no potential benefits from this clinical trial. So the objectives for my talk will be to briefly review the rationale for intratumoral immunotherapy of prolurassic cancers. I'm gonna provide you with an update on an exciting ongoing clinical trial that I briefly just mentioned. And then I'm gonna lead you into the future, I hope, with prospects for the future development of combined local and systemic immunotherapies for lung cancer, and hopefully we can all work on these together. So this is a slide that you've seen from many of our speakers, and rather than going in great detail, I'm gonna say that I'm going to jive a little bit on what our last speaker said, in which he talked mostly about the fact that we need to improve tumor delivery of agents. And I would argue that that's exceedingly important, but we also need to learn more about the nature of the tumor and the microenvironment of the tumor so that immunotherapy is delivered to tumors can be more effective. And going back to this concept, this concept of local delivery, but global action, I think this is really where we're headed. And again, this sounds like science fiction, the ability to inject a variety of compounds into a tumor to affect the interaction between the primary tumor, the regional lymph node, and the circulating T cells to then create a antitumor immune response, which is systemic, which can synergize with systemically delivered immunotherapies and other therapies. But I will show you, I hope, that there is some preliminary evidence that this is more than just science fiction. This is current science fact, and we need to develop this further. So this, for example, is one clinical trial done not in lung cancer, but in a refractory follicular lymphoma. This was a series of patients treated at Mount Sinai Hospital in New York City, published three years ago in Nature Medicine. So this is where patients had diffuse adenopathy. They were injected in one site up in the left supraclavicular region with two compounds. One is a TLR agonist, a toll-like receptor agonist, as well as a FLT3 ligand. Multiple injections intertumorally given under ultrasound guidance, and then in combination with a systemic anti-PD-1 monoclonal antibody, which by itself does not have a lot of activity in lymphoma. And what you can see in the pre- and post-PET CT scans is dramatic response, not only in the area where the injections were given, but at distant abscopal sites. And if you look at the pre- and post-biopsies, before and after the local injections, you see a significant infiltration of CD8 T cells into the tumor microenvironment after injection of these local immunotherapies in combination with systemic PD-1. This is a clinical trial done at Memorial Stone Kettering by a colleague and friend, Prasad Idusamili, who's a thoracic surgeon there, in combination with the interventional pulmonologist and radiologist there at Stone Kettering. Here they're injecting mesothelin-directed CAR T cells into the pleural space. In this particular patient with a biphasic mesothelioma, it was a percutaneous injection under CT guidance. By itself, the CAR T cells did very little, as you can see in the first PET CT scan from June of 2017. But after addition of an anti-PD-1 monoclonal antibody, which by itself does not have a lot of activity in mesothelioma, showed a near-complete response of the mesothelioma, and you see pre- and post-biopsies with only fibrosis in the biopsies after the delivery of the CAR T cells and the anti-PD-1 monoclonal antibody. I've been working for several years on another novel immunotherapeutic. This is a replication-incompetent adenovirus expressing the herpes simplex virus thymidine kinase gene. This is essentially a prodrug, which is activated in cells that express this gene when oral agents like acyclovir or valcyclovir, Valtrex, are given. When you inject this into the tumor, the adenovirus itself acts as a super antigen, and then the tumor cells die when they have the triphosphate formulation of the valcyclovir, kill tumor cells. This combination induces tumor infiltration of CD8 T cells, systemic immune responses, and importantly, as I'll show you, also upregulates PD-L1 on both tumor cells and infiltrating immune cells in the tumor microenvironment. So my former team at the University of Pennsylvania, led by Sunil Singhal, Steve Elbelda, my mentor, and Andy Haas from the Penn IP team, several years ago conducted a window of opportunity clinical trial in which they took patients who were about to undergo surgical resection of stage one to stage three non-small cell lung cancer. They did bronchoscopy, which was indicated for diagnosis and staging up front. In some cases, this was for percutaneous biopsy as well. And at the time of that standard of care procedure, injected a single dose of CAN249. Patients then got oral valcyclovir for two weeks, and then underwent their planned surgery on day 21. Tumor samples were obtained at baseline and afterwards, and multiple peripheral blood mononuclear cells were assessed during serial time points during the trial. And I'm just going to cut to the chase and say that what they're able to show using flow cytometry from both analysis of the tumor and the peripheral blood was significant upregulation of CD8 T cell infiltration to the tumor microenvironment and in the peripheral circulation, as well as PD-L1 expression, both on tumor cells, as well as infiltrating immune cells within the tumor microenvironment. And this is very important as we think about combinations going forward in the future. They also showed that this injection of CAN249 with oral Valtrex by itself, with no concomitant anti-PD-1 mononuclear antibody, can lead to significant tumor regression. So there's monotherapy activity in patients, and this is the repeat CT scan day 22 in a refractory sarcomatoid carcinoma just prior to surgical resection. So this phase one window of opportunity trial led to the current ongoing multi-center phase two clinical trial of intratumoral CAN249 in combination with ICIs, immune checkpoint inhibitors, and stage three, four non-small cell lung cancer ongoing at about 12 centers in the United States. These are patients with stage three, four non-small cell lung cancer, which is not resectable, who are on frontline immunotherapy or chemoimmunotherapy with an inadequate response in three cohorts. One cohort, cohort one, is those with stable disease after 18 weeks of their immunotherapy or chemoimmunotherapy. Cohort two is those who have been on therapy for 18 weeks and have evidence of progressive disease, and cohort three, which turns out to be a very difficult cohort to treat, is those who are immediately refractory. They've had disease which progressed right away after administration of standard of care frontline therapy. Patients in this trial stay on their standard of care therapy, so they're tolerating it, they have no immune-related adverse events, and they get two doses, either percutaneously or bronchoscopically, of CAN249, and each dose is followed by two weeks of valciclovir. They continue on their standard ICI or chemo-ICI, and then have serial blood for biomarkers. Primary endpoint is response by resist and safety, and secondary endpoints, survival, progression-free survival, quality of life, immunological biomarkers, et cetera. So this is myself, Dan DaCosta, now an interventional pulmonologist at Albert Einstein, and Vivek Murthy, who's the primary interventionalist involved in the study at NYU. Here we're using endobronchial ultrasound to inject a lymph node, a right paratracheal lymph node, with CAN249, and we're able to actually visualize with E-BUS the different sites, the different quadrants within the lymph node that we're able to inject pre and post. We're also able to use robotic bronchoscopy. Here we're using the ION system with a PSIOS spin for 3D confirmation, and radial E-BUS with that for confirmation of the device and lesion prior to intratumoral injection. So we presented the initial data from this study in June of this year at the American Society of Clinical Oncology meeting. This is the data from the first 35 patients. Again, we're continuing to enroll with a target of about 96 patients nationwide. We hope to finish within the next six months. What you see is the age range of about 70 on median, both men and women, a little bit more, few more men than women. Most of these patients are former or current smokers, and they have good ECHI performance status. And I point you over here to this waterfall plot, which shows that these patients, the majority of whom were in cohort two, which were patients who were progressing at the time, you'll see that the majority of patients, despite progressing, entering the trial, experienced some reduction in tumor burden with at least two patients having partial responses, again, progressing, entering the study. These are just a couple of the patients. This is a patient from the University of Pennsylvania who had a very large mass extending across the right upper lobe, across the minor fissure into the middle lobe with two injections at baseline and at week six with a dramatic reduction in the size of the tumor. This was one of the partial responses that was seen in the study. And this is a patient from NYU, which is very provocative. So this is a patient with multifocal disease throughout the body. We injected into the sub-coronal lymph node at baseline and at week six. This patient had a very bulky palpable supraclavicular lymph node and had marked regression, not only in the sub-coronal lymph node, but in the uninjected supraclavicular lymph node in which we demonstrated an abscopal effect. Again, this is in combination with continuation of the standard of care therapy for this patient. We also had the benefit of pre and post biopsies. And what you can see here from one representative patient is the evidence, and you can see the pre at the top and the post in the bottom, the number of pink cells, which are the CD3. These are the T cells infiltrating the tumor microenvironment that you can see very well post. The second one in is a little bit harder to see, but the light blue are the tumor cells. You see a significant reduction in tumor cells, and the dark blue, which doesn't come up enough, are the CD8 cells, which are the cytotoxic T lymphocytes. And so what you can see is a significant increase in infiltration in the tumor microenvironment as we had seen in the window of opportunity trial. And also, as I mentioned, we're getting systemic bloods in these patients. We're able to show that compared to prior to injection, a significant induction of interferon gamma producing CD8 positive and CD4 T cells that are circulating in the peripheral blood, which we hope correlate with systemically activation of anti-tumor immune responses. So the preliminary conclusions from this ongoing study is that this treatment, this combination of intratumoral CAN249 plus valciclovir in patients with advanced non-small cell lung cancer in an adequate response to first-line therapy who continued eyesight treatment is well tolerated, that we see promising preliminary activity with evidence of some disease regression in both injected and uninjected lesions, this abscopal effect that you had heard about, that in the cohort two patients, these are patients who are progressing at the time of entering the study, they have a disease control rate of about 88% with durable disease stabilization over several months in 10 out of 16 patients. As I mentioned, we had a couple of partial responses in the early series that we published and we showed evidence of both local and systemic anti-tumor immune responses. We're now planning a multicenter, hopefully multinational phase three randomized controlled trial, and we're really interested, and I'll get to this in a minute, the potential applications for this and other immunotherapies in early stage lung cancer. So many of you may have had the privilege of hearing from Patrick Ford earlier in this conference. Patrick is a leading thoracic medical oncologist from Johns Hopkins who is the lead author from this seminal paper published in the New England Journal of Medicine just this past May, which showed that neoadjuvant nivolumab anti-PD-1 monoclonal antibody in combination with chemotherapy was superior to chemotherapy alone as neoadjuvant treatment in resectable lung cancer. What they saw was a marked improvement in pathologic complete response in the patients who had combinations of chemoimmunotherapy and significant improvements in event-free survival. This led on the basis of the pathologic complete response data alone to an FDA approval for neoadjuvant chemoimmunotherapy in early stage non-cell lung cancer, which was truly revolutionary. But I would encourage you to go to the supplementary data. In the supplementary data from the paper, you can see that on the left-hand side, those patients, about 45% of the patients entered whose tumors were PD-L1 negative, they had less than 1% expression, did not benefit from upfront chemotherapy and immunotherapy, whereas those with very high PD-L1 expression had a dramatic benefit. So almost all the benefit from this trial was from those patients who had high PD-L1 expression. The same data, if you look at the supplementary data, is true for tumor mutational burden, which can be a surrogate for intratumoral T-cell infiltration. So I would propose that we have the ability to identify these patients upfront and convert the PD-L1 low and TMB low cold tumors to PD-L1 high hot tumors that can now respond to this therapy. So we need to do this. We need to be able to analyze upfront what's going on in the tumor microenvironment, from tissue sampling, from peripheral blood, from looking at historical material that we have from prior biopsies and clinical information. We need to put all this together using all the sophisticated techniques that we have, looking at all these biomarkers, and then we need to put them in a paradigm where we have not a one-size-fit-all, but a precision approach to help patients. So what is the future of intratumoral treatment for thoracic malignancy? Can we affect both local and systemic disease while decreasing toxicity? Well, I would argue that one of the things we'll be doing in the future is neoadjuvant intratumoral immunotherapy, possibly at the time of standard-of-care robotic bronchoscopic biopsy and EBIS staging, to be followed by systemic chemoimmunotherapy and resection, in which we're going to be doing this to expose tumor neoantigens in a proper setting, generating intratumoral CD8 T-cell infiltration, simulating a high TMB environment, and enhancing local immune response by increasing PD-L1 expression, both on tumor cells as well as in stromal cells in the tumor microenvironment. But I believe we're going to be doing precision-guided, based on all the biomarkers we just talked about, intratumoral and intranodal delivery of checkpoint inhibitors, which may work better locally than they do systemically, and use them in combination with systemic checkpoint inhibitors. And lastly, working with our radiation oncology colleagues and our interventional radiology colleagues, I believe we're going to be including combinations of local therapy with percutaneous or bronchoscopic ablation and intratumoral immunotherapy to synergize these effects. Thank you very much for the invitation.

intratumoral injections

lung cancer

historical background

evolution of intratumoral therapies

benefits of intratumoral injections

administration techniques

tumor microenvironment

intratumoral immunotherapy

combination therapies