Good morning, everyone. My name is David Pritchard. I'm going to be the moderator for today's talk. I'll just get a few logistics out of the way. If everyone could silence their cell phones as to not distract our great speakers. You will have access to the slides and the recording of the presentation after Congress is done. All speakers will disclose any personal conflicts they might have, and if we could hold questions to the end of all the speakers, they will join on stage, and we will be able to answer all your questions at that time. So today, we're going to talk about new therapies oncology is bringing to the ICU. Our first speaker today is Dr. Steven Pistorius from the Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, who will be talking about What's That Mab? Good morning, and thanks, David, for that introduction. I'm glad to see a fair number of you coming into a session like this. So I'll be talking a lot about the Mabs. You'll hear about the MIBs. You'll hear about CAR-T. So I hope these are cases that will interest you, and we're supplying the didactic information to help us manage our patients in the intensive care unit. These are my disclosures. There's nothing in the content of my presentation today that reflects any of these disclosures. So I'm going to review the history, the specific targets and indications for why we use monoclonal antibodies to treat patients with cancer, talk about some of the most common organ toxicities associated with select monoclonal antibodies, and then finally, talk about some of the treatment strategies to manage some of these toxicities. Antibodies, as you know, are proteins produced by B cells of the immune system. A lot of credit to Paul Ehrlich, who won the Nobel Prize for Medicine in 1908, because in the late 1800s, Ehrlich actually provided us with a side chain theory, which postulated that there are side chains or receptors that bind antigens that are usually associated with cells or distributed in the bloodstream to attack a foreign antigen. And that basically was the foundation or the basis for chemotherapy. At that time, in the late 1800s, Ehrlich was using chemical dyes to treat various diseases. So he actually invented the concept of the magic bullet to fight diseases, including cancer. Fast forward to 1975, when Milstein discovered the idea of the hybridoma technology that paved the way for the discovery and formation of the first concept for murine monoclonal antibodies. But it took another full 20 years after that, in 1997, for rituximab, the first murine-derived monoclonal antibody, to get approved by the FDA to treat relapse lymphomas and follicular lymphomas. And then a year later, trastuzumab, a drug, an antibody that's used for breast cancer. And then the history goes on. And now we have over 30 approved monoclonal antibodies to treat a variety of conditions, but most of them to treat cancer. If you look at this slide, you'll see that over the last decade or so, there's been a tremendous increase of the number of antibody therapeutics that are entering first in human studies. Most of these studies have been done first in human inpatients with cancer. And the list will continue to go on as more discoveries come about. So on the right-hand side of the slide is shown a schematic of how an antibody looks like with a constant region and a variable region. It is on the variable region where the antigen binding site is, and that binds the target cells. And depending on which antibody you're using, to which receptor or side chain it's supposed to block, that is how the monoclonal antibody is used to identify specific receptors on cancer cells and targeting specifically only those target cancer cells. How do they work? They work by a variety of mechanisms, including direct lysis of cancer cells to immune-mediated mechanisms, block of cell growth, as we'll see with HER2, blood vessel growth can be inhibited, and then they can also be used to block immune system inhibitors as well as deliver radiation therapy, so-called radio immunotherapy, or even deliver chemotherapy, as we've seen with antibody drug conjugate. There are four general types of monoclonal antibodies. There's the murine-type antibody. There's the chimeric, the humanized, and the full human monoclonal antibody. So all of the MABs end with the MAB. The stem is the MAB, and then there used to be, up until two years ago, a sub-stem, we called it, where depending on where the antibody was originally structured from, whether it was mouse, chimeric, human, or fully human, then they had sub-stems such as O for mouse, C for chimeric, Z for humanized, and U for human. But in 2017, they went away from that, so they no longer follow that strict classification, but that's how you would remember. So if you see a MAB that has the word O in it, it's murine-derived. If you see one that's ZU, Z-U in it, so allantoosamab, for example, that's a humanized, and then if you see one like adalimumab, that's a human-derived antibody, so with the sub-stem U. But again, they went away from that very, very recently. So there are many indications why monoclonal antibodies are used in cancer patients. We know this in hematologic malignancies, as you might see with rituximab to treat lymphomas, to allantoosamab to treat and target CD52. So it depends on what the targets are for hematologic malignancy patients. Then the monoclonal antibodies are designed for those specific receptors. Similarly, for solid tumors, there are a variety of solid tumors from colorectal, breast, melanoma, prostate, stomach cancer, head and neck cancers. Again, selecting specific targets like HER2, epithelial growth factor receptor, VEGREF, vascular endothelial growth factor, these are designer monoclonal antibodies that specifically target, and based on their target, it's how they actually work in treating patients with cancer. So a VEGREF inhibitor would be blocking vascular endothelial growth factor that basically allows the blood vessels to continue growing and peripherate and therefore feed the tumor, if you will. So the antibody is designed to stop that inhibitor from doing that and therefore prevent blood vessel growth in these patients. So a lot of what we're going to be talking about today actually is very fresh in the literature. Our group from the Oncological Critical Care Network just published a few weeks ago, Critical Care Management of Toxicities Associated with Targeted Agents and Immunotherapies for Cancer. If you had one good reference to go, I would suggest this article because a lot of the talks today are going to have a lot of the material that we'll be discussing. So within that article, we have separate tables. I'm going to only talk about monoclonal antibodies. Shown here are about eight of those monoclonal antibodies, their targets, their indications, and more importantly, for the topic of today's presentation, what the different toxicities are. And we arrange them by organ systems because this is what intensivists and clinicians in the ICU usually like to think. We like to think of what organ system is deranged, and then we try to know the toxicities associated with that and how to manage those types of patients. So we divided this into unique toxicities, if they're specific unique toxicities, but more commonly, pulmonary and neurotoxicities and cardiac toxicities really are most of the toxicities besides infusion reactions that we concern ourselves when we give a monoclonal antibody to treat a patient with cancer. Besides those, since the article got published, there are a few more newer antibodies, including these three that are listed here, which are all anti-CD20 directed antibodies. The only reason I brought this up is there are two blocks, block box warning on a couple of them. The first two listed up there, which can cause hepatitis B reactivation, and then this dreadful syndrome of PML or progressive multifocal leukoencephalopathy. This is something that certainly from time to time we get to encounter, particularly those associated with JC virus infection. These are the toxicities that I just want to go over very quickly. Infusion reactions, cytokine release syndrome. You're going to hear a little bit more about cytokine release syndrome when we talk about the topic of CAR T cell therapy. Cardiac toxicity certainly can be a problem. Pulmonary toxicities, renal as well as neurotoxicities. So I think you all know in 2006 there was this publication of a very, very serious set of adverse reactions that occurred on six volunteers that were treated with an anti-CD28 monoclonal antibody TGN1412. This basically told us, hey, don't go too fast. Your first in human trials can be associated with a lot of serious toxicity. These were six volunteers who within hours of getting this monoclonal antibody developed a severe sears response that subsequently got associated with shock, respiratory failure requiring vasopressors and mechanical ventilation. Two of these patients required very intensive and very long stays in the ICU between 8 and 16 days. Luckily, every one of those patients, volunteers I should say, survived. But it told us a lesson that you have to be very seriously monitoring these patients because they are at risk for a lot of the serious things that we see in patients with sepsis or septic shock. But this was a severe immune adverse reaction to this particular monoclonal antibody. So infusion reactions can be serious. They're commonly IgE mediated unlike CAR T which is more immune or cytokine mediated. So they commonly occur between 30 minutes to about two hours after the initial drug infusion. The signs and symptoms are like what you might see with somebody with anaphylaxis or severe anaphylactic shock. The first dose reaction can be combined with other things that we see in cancer patients that get treated for cancer and that includes tumor lysis syndrome, cytokine release syndrome, et cetera. So this is something that you have to be familiar with. The pathophysiology involves an antigen antibody reaction that triggers cytokine release. So TNF, IL-1 and all the other bad mediators out there when exaggerated in their release can cause a variety of the signs and symptoms that we see in these patients. Our management like we do for any serious adverse reaction or anaphylaxis of course is epinephrine fluids, H1H2 blockers, use of corticosteroids. Patients may require airway and intubation for severe respiratory failure as a reaction. And then many patients are kept on epinephrine infusion or other pressures for shock and then desensitization. If you are going to retreat the patient certainly sometimes, you know, you probably are going to need an immunologist here to come in and do some desensitization procedures and maybe or choose another agent if the patient has had a very serious adverse event with that monoclonal antibody. You should know that some reactions can be delayed. They are rare fortunately. This was a patient that was published in JCO in 2008 that got citoximab, metastatic colorectal cancer patient with hepatic metastases. Got citoximab, started up having diffuse macular papular lesions. Initially was thought to have Stephen Johnson's and then this very, very rapidly within hours to a few days, developed into a severe blistering erythroderma and severe reaction that we now call toxic epidermal necrolysis or TEN. So you can have both acute infusion reactions or you can have delayed infusion reactions. The treatments are generally more or less the same but recognize that some of these things can manifest at a later time point. Shifting over to cardiotoxicity, acute coronary syndrome certainly has been reported with bebasucimab and trastuzumab which is a drug used for metastatic breast cancer patients. Cooney's syndrome, for those not familiar, we'll talk a little bit about that. You see that with three monoclonal antibodies. Cardiac dysrhythmias can sometimes be very common and may be a reason to monitor the patients in the IC if they're getting these drugs and then of course cardiomyopathy. So Cooney's syndrome, for those who may not be familiar with it, this is like a hypersensitivity coronary syndrome. Looks like ACS but it's actually mediated by mast cell activation and other inflammatory cells. It looks like you're having an acute coronary syndrome. You have ST elevations. Looks like a real MI but it's actually a reaction of the myocardial cells to the immune product, in this case, the monoclonal antibody. There are three variants, types 1, 2 and 3. Type 1 is somebody with no predisposing risk factor for coronary artery disease gets an antibody and then develops a coronary artery spasm. This may be associated without an increase in cardiac enzymes like troponins or CKs and may occasionally have no reason to progress the coronary artery need for coronary intervention. Types 2 and 3 are generally those with either preexisting but quiescent atheromatous disease with release of mediators that again may be associated with normal cardiac enzymes and troponins or may actually have plaque rupture and manifest like we do with acute myocardial infarction. And then type 3, CUNY syndrome, are the patients that have stent thrombosis associated with it. The treatment of CUNY syndrome, because it is a hypersensitivity reaction, it's basically treated the same way. And then in patients that have actually evidence of coronary artery disease, then of course they'll need coronary interventions. Type 1 responds well to corticosteroids, H1H2 receptor blockers and coronary vasodilators like nitrates and calcium channel blockers are, are sometimes necessary. For types 2 and 3, of course, you're going to often require coronary interventions. In this particular case, a beta blocker, which we generally use for acute coronary syndrome, may sometimes make epinephrine, which we're going to need to use, sometimes ineffective. And so you might need to reverse, if there are a lot of beta blockers on board, you may need to reverse that with giving glucagon first. And one particular important pain medication to avoid is morphine, because this is a mass cell activation histamine release reaction, so you don't want to be using morphine, because that's going to aggravate that. So in these patients, fentanyl will be the favored analgesic to use. Cardiomyopathy is also a well-known side effect of some of these monoclonal antibodies, in this case trastuzumab. It's most commonly associated with reduction in left ventricular ejection fraction, and there is a lot of new understanding of how the mechanism of cardiomyopathy occurs in these patients. And it typically involves some activation of systems, such as MOP and cytochrome C release, as well as caspase activation. And those mechanisms are felt to be the end result with the apoptosis of cardiac muscle cells, which then leads to decreases in myocardial contractility and decreases in ventricular function. Some of the landmark trials with trastuzumab that demonstrated toxicities are shown here, two articles, one from the New England Journal and one from JCO, published in 2011 and 2012, showed that the combinations that use trastuzumab were definitely reported to have a higher incidence of death or congestive heart failure. And similarly, these were patients that were more likely to have an increase in more than 10% in reduction in left ventricular ejection fraction. So anyone that is at risk for developing cardiac toxicity from trastuzumab really has to be screened, because they tend to be the patients that will have a higher likelihood of developing congestive heart failure, even at risk for sudden cardiac death. So who are the patients to worry about? Anyone that's been previously exposed to anthracyclines, because anthracyclines are inherently cardiotoxic. So if you add a trastuzumab to somebody that's already been exposed to anthracycline, you're going to risk more cardiotoxicity. Anybody that's starting with an EF below 55 would be at risk, 55%, the older patient, the patients with elevated BMI, hypertension, and other risk factors for cardiovascular disease. The standard treatment here, just like we do for patients with heart failure, would be, again, the use of angiotensin converting enzyme inhibitors, as well as beta blockers. Shifting over to pulmonary toxicities, again, commonly interstitial pneumonitis will be something that you might expect with cetuximab and trastuzumab. Some patients will very quickly go into ARDS. Luckily, that's not very common. Bronchospasm can be associated with these antibodies, as well as thromboembolic disease, particularly with the VEGF inhibitors, such as bevacuzumab, and then you have to think long-term about BOOP, bronchiolitis obliterans, organized pneumonia, which also has been reported with retuximab. Treatment here, just like we do for patients with pneumonitis or ARDS, is generally supportive, and in severe cases, the use of corticosteroids. Renal toxicities, again, they run the gamut from interstitial nephritis, tumor lysis syndrome, thrombotic microangiopathy. The challenge is that many of these patients are already at risk for some of these based on whatever other treatments they've received. So on top of that, if they receive a monoclonal antibody, it can sometimes make things worse, and the picture can sometimes be muddled. So it's okay if you don't realize right away that this is a side effect of the monoclonal antibody, but if you have a patient that is developing some acute kidney injury or at risk for renal failure, then you need to make sure the cardinal principles of managing these patients, you know, hydration, avoiding nephrotoxic agents, you know, using resveratase to lower the uric acid, and in patients that may need renal replacement, of course, you're going to do that. For thrombotic microangiopathic problems, though, there is a anti-complement that you can use, which is ecolucemab. So this is one specialty drug with a MAB that is very specific for a complication related to these patients, which is thrombotic microangiopathy. Neurotoxicities is another big organ toxicity, and there are at least three major ones. Bevacuzumab, cetuximab, and trastuzumab are known to be associated with neurotoxicities. There are a variety of presentations. This is very similar to what we sometimes see in bone marrow transplant patients, because they can also be at risk for some of these, like those who take calcineurin inhibitors, for example, would be at risk for PRESS, posterior reversible encephalopathy syndrome. But then other patients may be susceptible to strokes, bleeds, aseptic meningitis, encephalopathy, progressive multifocal encephalopathy with certain agents. So these are things that, you know, oftentimes when a patient is altered or confused, it may be difficult right away to attribute that to one of these antibodies. As long as you know, you know, that certain antibodies may be associated with these issues, then you might have a faster way in understanding, you know, that they might, in fact, be responsible for it. PRESS is a very interesting syndrome. It's called a brain capillary leak syndrome. It's related, these patients have very high blood pressures. They can have visual changes. They can get fluid retention. A lot of this is injury to the vascular endothelium of the brain. Again, you have vasogenic edema. Most often, the posterior white matter is involved. This is felt to be related to endothelial dysfunction and can be quite common in some patients that receive a VEGF inhibitor, like bevasucimab, for example. The treatment here typically is to discontinue the drug that they've been getting that might have led to it. And, of course, blood pressure control. Let's just highlight a case of PML in a 62-year-old woman with progression of CLL. She gets two cycles of obinutuzumab and clorambucil. There's a past history shown there. She gets progressively worsening blurry vision. The rest of her exam, including her eyes, are unremarkable. And this is her brain MRI. If you do a CT scan, which generally might be the first scan that you might order, you're just going to see, like, hypodense lesions. It won't be as characteristic because we see a lot of hypodense lesions on CAT scans and don't know what to make of it. Did they have a stroke or did they have an infection? It's hard to say. But the brain MRI can be very, very classic in PML. And this one just kind of highlights for you the progressive leuko, massive leukoencephalopathy of the brain, the softening of the brain, destruction of the brain cells. So this is something that is very characteristic. And this is the MRI for this particular patient. So a diagnosis of PML was made because of radiologic progression. She was not improving with standard therapy. And then they confirmed on her CSF fluid analysis that she had the JC virus positive on it. She progressed very quickly with rapid connect cognitive and neurologic deterioration. IVIG was given without benefit. And this patient survived this hospitalization. But as you can see from this case report, six months after the first occurrence, she still is very seriously disabled. So this is something that might be less reversible, even if you discontinue the drug and even if you do a lot of supportive therapy. So it's something that you have to recognize that can be a serious issue. There are unique toxicities, especially for ALL. I just listed a few of them. As I mentioned earlier, hear more about CRS. Veno-occlusive disease is another that you have to consider. These are therapies for ALL, which is one of the more common pediatric cancers that you might be seeing some kids and early young adults being treated in your intensive care units. So cytokine release syndrome can involve every organ system. And there are specific antibodies that we give. You'll hear about that more in the subsequent talks. I just want to highlight one of those, since this is a Blender-to-the-Map case of CRS with HLS, and you can see very high levels of ferritin in blue, very high levels of temperature, 41 plus, shown in red, very low levels of fibrinogen, shown here in black. So these are the classic hallmarks that you'll get to see in a patient that is developing HLH-like syndrome or CRS syndrome. As a result of this antibody, this patient got this IL-6 inhibitor called TOSI or tocilizumab, and that basically reversed. You can see the drop in ferritin, the drop in temperature, and the climbing back of the fibrinogen is the DIC result. So this is like a classic set of syndrome that you'll see in terms of how these patients may respond, and in this case, luckily, the patient survived and reversed her condition. VOD or sinusoidal obstruction syndrome, as it's more popularly known now. Again, this is not unique to just the antibodies. We see this in patients that have bone marrow transplant, particularly the allogeneic transplant patients, they can get this. So the triad here is right upper quadrant pain, jaundice, ascites, and hepatomegaly. It's a unique syndrome in that the hepatic venous sinusoids are what's occluded, not the macro, not the large vessels, the small venules. And so the treatment here is usually supportive care, attention to fluid balance, because they already have ascites and they retain fluid, keep their intravascular volume adequate, avoid hepatotoxins, of course, and then in select cases or in severe cases, using a local thrombolytic agent, that's defibrotide, usually for about three weeks. What is important in understanding these toxicities, and I think will be a theme of all our subsequent talks, is that you need system-level approaches to manage toxicities, not just with the MABS, but with the checkpoint inhibitors, with the CAR-T, and this emphasized the need for a lot of patient education, not only patient, but also clinician education, for those who may not be seeing these cases more frequently out there in the community. You know, you might see a patient with colitis or pneumonia, but they actually may be a result of some of these antibodies or checkpoint inhibitors. So patients, clinicians, practicing need to be continuously informed. You need to have pharmacy guidelines, order sets, institutional initiatives, and global reach, and spread it out to the medical community that these are toxicities that more and more, as more and more patients with cancer get treated with these novel therapies, you are going to see this, not just in academic institutions, but out there in the communities where you're practicing. So again, it reinforces the need for system-level approaches to managing these patients. So in summary, what I just wanted to do in my short talk was just to kind of let you be aware of some of the potential toxicities associated with each of these agents, identify patients with high risk and try to prepare them, anticipate what toxicities they're going to have, appropriately manage them, like you would do in most cases, supportive care, steroids, and maybe other supportive modalities like mechanical ventilation, arena replacement. If they have CRS, HLH, then they might need other agents like ecolizumab for TMA or tocilizumab for CRS. I mean, it will depend really on what kind of syndromes they're getting. And again, the focus on the need for multidisciplinary team approach, because that is the only way. We can't do this by ourselves. We need our primary oncologist. We need our nephrologist. We need our infectious disease. We need our pharmacist. It's a team game. It's not something that we should just do on our own. Thank you very much. Thank you very much. Our next presenter will be Dr. Joseph Nates from the University of Texas MD Anderson Center, who will be talking about ICU complications of checkpoint inhibitors. Thank you very much for the presentation and the invitation. So as mentioned, we're going to narrow a little bit the subject. And among the monoclonal antibodies, you have this particular group of checkpoint inhibitors. I don't have any conflict of interest to declare. The objectives of my presentation are basically three. Increase awareness about this problem. Identify the most frequent types of adverse events and discuss the management. The subject is very extensive, so I'm going to try to focus on the ones that we actually see in the ICU. What are we talking about checkpoint inhibitors? Why is this so important? Well, it's important enough to receive a Nobel Prize. So you have here Dr. Honjo and Dr. Allison that were the pioneers in developing this strategy of therapy in which the immune system is manipulated as a weapon. And the outcomes were really outstanding. There were patients that received the first dose and basically the cancer disappeared, patients with melanoma initially with the CTL4 inhibitor. So this therapy is still not available everywhere. It's extremely expensive. Some of the therapies cost like $140,000. And of course, it's getting cheaper, but it's still very expensive. And there is a tremendous amount of toxicity associated with it. But the price to pay is worth it. So we're going to talk about the checkpoint inhibitors here. You can see the activation therapies. There are many of them. Among them, the monoclonal antibodies, and this is the particular group. The other suppressant therapies that have been more traditional like steroids, et cetera, are not that relevant today. So these are the receptors, the program death one inhibitor checkpoint, and the ligand. And these are the medications that target these particular receptors. And the other one is the CTL4. And you can see that once they are inhibited, the cells are disinhibited, inactivated, and immediately start to release all the inflammatory cytokines and are able to destroy the cells. What is amazing, though, is that these have only been approved in less than 10 years ago. The epilimumab, you can see here, was approved in 2011. And all this, as you can see here, is after 2015 for the different indications. You can see for lung cancer, for renal cell cancer, for Hodgkin, et cetera, et cetera. And the explosion of medications that are coming out, the pipeline continues to increase. And this reminds me that once you inhibit these receptors, it's like releasing can. You know, it helps to destroy your enemy, but you can have tremendous consequences, a lot of devastation as a result of these activities. And you can see here all the types of toxicities it can produce. I think every single thing you can find in Harrison's textbook is here. So you have neurotoxicity, pulmonary toxicity, and others, liver toxicity, colitis, et cetera, et cetera. Things that can produce your risk is being female or receive steroids with the therapy. And things that can increase your risk is having an autoimmune disease before, have a severe kidney disease, or receive a CTLA for inhibitor. These are the guidelines that were published in 2017 from the European Society of Medical Oncology. And you can see here the adverse event rates. Grade 1 to 2, 60 to 85%, okay? Grades 3 and 4, which are already to deliver that require hospitalization, and 4 require ICU admission, 10 to 27%. When you combine these two inhibitors, the PDE, PDL1, and the CTLA4, you can have a 95% of grade 1 to 2, and up to 55% grade 3 to 4. And they can appear any time throughout the year. This is in weeks, so you can see here 50. And for example, call attention when you combine them, like you can see the orange is combinations. You can see an onset that is very early in nephrotoxicity. But it's only one. This can take us actually up to a year. A recent meta-analysis showed that in 125 trials and 20,000 patients, 66% of them develop some kind of adverse event. 14% of them develop a grade 3 or higher. With pneumonitis being one of the worst, with a relative risk of 24%. And associated with 28% of the fatalities. You can see here the table of the 82 patients that die in this series, and pneumonitis as the first culprit. When you look at them per groups, you can see that CTLA4 inhibitors are more associated with gastrointestinal toxicity. One in four of the patients that die in this series of 39 patients had severe colitis. And when you're talking about PD-1 inhibitors, pulmonary toxicity and cardiac toxicity were the culprits. So in general, about all the patients that complicate 3% of the patients die. One of the most serious problems we have is respiratory failure. And many of these patients present in respiratory failure from pulmonary toxicity. So the criteria for adverse events goes from one to five. Five, you're dead. You know, and one, you know, you may not even know that you have a problem. But when you start to become symptomatic, you are supposed to stop the checkpoint inhibitor and start steroids, oral steroids. And start to have very close monitoring. When you start to have problems with your daily activities, you probably need to be hospitalized and start to receive steroids IV. So these are the multiple problems that you can find with these high-risk agents. They can present with this neobronchospasm, cough, et cetera. All the symptomatology we are used to. And the therapies go from steroids, anticoagulants, antibiotics if you have an infection or a pulmonary embolism. Bronchohilators, oxytotherapy, et cetera, et cetera. As you can see here, in all these agents, the monoclonal antibodies and the checkpoint inhibitors are usually associated with pneumonitis. You can see the receptors here all distributed broadly. Now, when you look at the presentation and you do a CT or just X-ray and MRIs, et cetera, there is a broad range of pathologies you can see. The most pathognomonic is the ground glass opacities and sometimes kind of patch opacities bilaterally. But you can find in the same patient multiple additions. This is kind of a classic case, a 46-year-old presented with metastatic small cell carcinoma. Start to complain of dyspnea after one month of receiving pneumonia. And then after ruling out all infections, et cetera, the patient is started in steroids and pneumonia and stop and the patient does better. This can be in multiple types of cancer, melanoma, head and neck, et cetera, et cetera. And you can see by the years of these case reports, this is very recent. So the cases are starting to pile up very rapidly. So the management of these patients is basically when you are a grade one, laboratories, follow-up, et cetera, and be very alert because at some stage, you are going to have to stop the checkpoint inhibitors and start oral steroids. If the patients don't improve or get infected, the patient need to be admitted to the hospital, switch to IV steroids, and sometimes require ventilatory support. If the patients do not respond, they may get infliximab, 5 milligrams per kilo. Other reason for admission to ICU is weakness in respiratory failure. So we see a lot of Guillain-Barre, myasthenia gravis, but, you know, there are many, many other problems that can present with these therapies. Patients can have seizures, status epilepticus, et cetera. Post-press, that was mentioned before by Steve. And this is a case series of Guillain-Barre. We used to see more Guillain-Barre at the beginning because the patients would call to the clinic, well, I'm very weak, I cannot stand up, et cetera. Oh, relax, you know, rest, and then come in a week or something like that. And by the time the patients will come, they were so weak that will need to be admitted to ICU and receive ventilatory support. So that's one group of the patients that we have seen. This is a little bit more rare. We haven't seen one of these cases, but this particular case report very well studied. Despite the classic therapy of status, plasmaphoresis, IVIG, et cetera, did not survive the event. We have seen myasthenia gravis as well. It can be induced or can be aggravated. When you have combination therapy, you see much more serious cases. And the treatment, again, as I mentioned, steroids, IVIG, plasmaphoresis, et cetera. Cardiology, this is more rare. We have seen several cases lately. Although if you look at the statistics, this is a database that has more than 12 million patients in which 31,000 of them receive immunotherapy. And when they receive immunotherapy, the incidence of myocarditis, you can see here, is less than 1%. CTLA-4, 0.07%. But when you combine them, it goes above 1%. Of course, the odds ratios go up when you compare to the populations that have not received these checkpoint inhibitors. You can see vasculitis, pericardial disease, et cetera. Other things you can see is arrhythmias. You can see atrial fibrillation. You can see ventricular arrhythmias. And AV blocks. There is a reason these patients need to be in a monitor bed with pacemakers at bedside if they present with any type of toxicity of this type. Mechanism of toxicity are many. It's not very clear exactly. In every patient, it could be different. But in the models in rats, well, in mice, sorry to the mice, have been reproduced. In patients that present with fatal myocarditis, you can see that there is upregulation of these receptors. Definitive diagnosis, usually with pathology, transvenous or transjugular biopsy. But you can use cardiac MRIs, echocardiograms to show wall motion abnormalities with the biomarkers, troponins, BNPs, electrocardiogram, et cetera. With less than that, you can have a probable problem or possible. This is the Vanderbilt approach in which they start to monitor very closely the patients if they present with any BNP or troponin elevation. When the patient have symptomatology, have acute changes in the electrocardiogram or echocardiogram, the patients are admitted to the hospital and start to receive steroids. And they may have to be in an ICU bed. Gastrointestinal, well, one of the most serious problems you see with these agents is diarrhea. You have one in 10 patients develop diarrhea. About one in 11 patients develop some type of colitis. As you can see here, all these receptors, at the moment they are disinhibited, inactivated, release a lot of cytokines that injure the mucosa. And you have here a list of all the complaints that the patients present with, from vomiting, nausea, abdominal pain, diarrhea, et cetera. They have usually edema. They can have crypts with micro-abscesses. They have denudation. They can have bloody diarrheas. And as you can see here, this is the overall incidence of all grade colitis, 9%, but grade 3 to 4, 7.9. Hepatitis of all types, about 1.9%. Now when you combine them, look at the jump from 1.9% to 17.6%. And in overall incidence of all grade colitis go from 9% to 14% almost. Now the doses also can affect the onset of these diseases. The incidence is 5% when you use EP at 3 milligrams per kilo. But if you increase it to 10 milligrams, you can double the incidence. And the management is, as I mentioned before, with respiratory, grades 1 and 2 are usually ambulatory. Grade 3 and 4, patients are hospitalized. It can be in the ICU. The checkpoint inhibitors are stopped. Steroids are giving IV. Antibiotics, if it's necessary. Supportive care, et cetera. Lastly, I want to touch on renal. Renal is kind of rare. In our hospital, we have a series of 10 years. We only have 16 cases. The pathologies that have been reported are so many that we cannot even get into this. But the most frequent is acute tubular interstitial nephritis. The incidence of renal toxicity goes from 2 to 4.5%. And these agents are not excreted through, metabolized through the kidneys or the liver, but undergo proteolysis. Lymphocytic infiltration is seen in the biopsies. But the management is a little bit kind of complicated here. But bottom line is, if you have some kind of proteinuria, maturia, or puria, the patient needs to be followed very closely and consulted a nephrologist as soon as possible. They may need biopsies if the proteinuria aggravates or they have tubular cells or red cells in the urine, et cetera. The treatment, again, the same. You stop the medication and give steroids. So as we have seen, this posture to these checkpoint inhibitors produces significant numbers of adverse events. The severity of illness type and stage of cancer can contribute to the severity of the presentation. Because it's not the same thing to have metastatic melanoma to the brain than to have lung cancer, extensive lung cancer, and then develop pneumonitis. Probably the second case will require ventilatory support, et cetera. Early recognition is important. As I told you, at the very beginning, a few years ago, we used to see a lot of Guillain-Barre. Now we are seeing less and less. Because we're stopping on time and giving the steroids on time. So critical care practitioners should be aware of this. Because this is not only happening in our centers. It's going to happen everywhere. As these FDA-approved medications are more available everywhere, you are going to see these adverse events in your center. And this is just to invite you to our Oncology Critical Care meeting in May. Thank you. Thank you. Thank you very much, Dr. Nates. Our next speaker will be Dr. Colleen McEnvoy from Washington University in St. Louis. And she will be talking about immune effector cell therapy and clinical presentation of common toxicities. Thank you. So I'm going to go over immune effector cell therapy, really CAR T cell therapy today. I have no financial disclosures. And talking about immune effector cell therapy, as critical care physicians, we really didn't think we'd go back to all this immunology. But it's becoming more and more important. And because of the toxicity, so we'll review the main two toxicities, which is cytokine release syndrome and immune effector cell associated neurotoxicity. Really, to get into it, talking about chimeric antigen receptor T cell therapy, what it is is a genetically modified T cell. So it's really using the patient's own T cells to attack tumor cells. And the T cells then recognize specific antigens on tumor cells that result in activation and cell proliferation that then ultimately leads to death of the tumor cell. It's considered a living drug mainly because it has a durable and lasting effect, which is really important for us to know because of the delayed toxicities that can occur. And it's generally autologous. However, there are these new kind of off-the-shelf CAR T cells that are being developed. And I think we'll see more and more of those. Just to give you an overview of what happens is, once a patient is identified as being a CAR T candidate, they receive pheresis. Those cells are then pre-specified with which antigens they want to use to target the tumors. So in this particular example, it's CD3 and CD28. And those are then activated. They then use a gene transfer mechanism through a viral mechanism. I'll show you another schematic of that. And then there's an expansion of the cells. And they wash and formulate them. Prior to infusion, the patient will receive a conditioning regimen with either fludarabine and or cyclophosphamide. So here's the schematic of where you have an inactive virus that's inserted into a T cell. And it develops this chimeric antigen receptor based upon those specific antigens that have been identified. The CAR T then latches onto the cancer cell. And then the cancer cell dies. This has been revolutionary, as you all know. But what happens when the cancer cell dies is where we come in and where the toxicities are at play. Just to review the FDA-approved CAR T therapies for adults is Chimera, which is for large B cell lymphoma that's relapsed or refractory after two lines of systemic therapy. And with Yaskarta, it's adults with relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy, including diffuse large B cell, mediastinal large B cell lymphoma, high grade B cell lymphoma, and diffuse large B arising from follicular lymphoma. Or you can create your own, which is occurring at a number of institutions. I'm going to quickly go through the studies that are really landmark studies in how these drugs became approved. And it really started with children and young adults in the Alinea study. It was 92 patients, 70% received infusion. And they had an overall remission rate of 82% with an intention to treat of 66%, which is unbelievably remarkable. And the fact that they also had relapse-free survival among patients was 80% at six months and 59% at 12 months. Remember, these are patients that really didn't have any other lines of therapy left and otherwise would have died. So this is really incredible. And then they did find that most of the relapses were CD19 negative. So the patients that did not have that CD19-specific antigen to allow for killing of those tumor cells. But what we found from this is that the adverse events that we want to focus on are the neurotoxicity and the CRS. And that occurred in majority of patients. If you look at any grade for CRS, it was 77%, and neurotoxicity, 40%. With a good number, about 40% of patients with CRS being grade 3 or 4. And about 13% being neurologic. The other thing I want to point out is infection. Infection is quite common in these patients as well. We are really modifying their immune system, and they are at risk of serious infection, which we'll talk about later. And then when we looked at adults, the Juliet study was in a CD19 positive diffused large B cell or follicular lymphoma with no curative treatment options. 64% had a response at three months, and 57% had complete remission at six months, and all remained in remission. And again, looking at the adverse events, you see similar rates of CRS and neurotoxicity. And here is, again, another study that led to the approval of Yaskarta, which looked at patients with refractory large B cell lymphoma. And again, it's similar. So what does that really mean for the intensivists? And what we see is that 15% to about 50% of patients in these trials required ICU admission. And in a pediatric population of patients with ALL, 35% of 75% patients were admitted to an ICU and required high-dose vasopressors, renal replacement therapy, and invasive mechanical ventilation. And so if we think about this and break it down, Elie Azoulay from France looked at this. And looking at the numbers, if you have 600 patients with ALL, 6,000 with lymphoma that qualify at this time for CAR-T, you're going to start seeing a number of patients in the ICU. So we all need to be ready. And that really doesn't even account for the number of trials that are coming out. So there are over 200 CAR-T trials that are underway and looking at all different forms of cancer. And some of these have not had good results. And some of them have fatal SAEs. And that's something that us being on the front line need to identify. So as a patient comes in having received one of these clinical trials, identifying the toxicities is very important. So what are those toxicities? As we've mentioned, cytokine release syndrome and then the immune effector cell-associated neurotoxicity syndrome, ICANS, previously just termed neurotoxicity. But you'll really see now in the literature that ICANS is the term that we're using. Tumor lysis syndrome is rare but can be fatal if not treated appropriately. I'm not going to review all of it. And Christina will talk more about some of the less common toxicities as well, like HLH and hypogammaglobulinemia, which are very important. This is really a compilation of all the studies that have been done regarding CAR-T therapy and the toxicities. The important thing to note here is that, number one, they're very common. The other thing to identify is that during this time, all the different studies use a different grading system. And so that kind of varies for the percentages of which patients had grade 3 versus grade 4. Now we've come up with more of a consensus grading system based upon a lot of this previous literature. So CRS really is a clinical syndrome. It's a physiologic response to the tumor cells. What happens is that the tumor cells become activated. And that leads to release of cytokines, most specifically interferon gamma and TNF alpha. And then that causes more activation of your monocytes and your macrophages. I'll show you a schematic here in a second. But once you activate your monocytes and macrophages, you then have release of more cytokines, including IL-6 and IL-10. And that's where our targeted therapies are. And we know that the prevalence really varies depending on the type of malignancy and the CAR-T construct. We are seeing less severe cases of cytokine release syndrome and neurotoxicity as these constructs have gotten a little bit better. But again, as the number of constructs are being developed, we'll still see more and more patients in the ICU. It occurs in about 60% to 90% of patients, with about 30% being greater than grade 3. And a good number will require high-dose vasopressors. The incidence and severity, again, depends on the tumor burden and how many cells are actually infused into the patient. It usually occurs within the first 7 to 14 days. But you can have delayed up to about 10 weeks. So the endothelium really is what becomes activated. And it's the important mediators of CRS development and severity. And again, it occurs when the CAR-T recognizes that tumor cell. And you can see higher rates of, or higher levels of CRP and pro-inflammatory cytokines. That has really correlated with the severity of CRS. We can use the CRP as a biomarker for the disease as well. And they have found that interferon gamma and TNF levels that are higher are associated with higher SOFA scores. So here is the schematic. Looking at, once you start proliferating, you get this release of TNF alpha and interferon gamma that leads to more of a flu-like syndrome. You have fever, headache, myalgias, nausea, vomiting. And then you can start to develop hypotension and hypoxia, mainly related to capillary leak syndrome. That can also lead to acute kidney injury. And then as more of the lymphocyte starts dying, you get more release of the cytokines through the macrophages and monocytes. And you particularly have IL-6 that's activated. The IL-6 activation can then cause more of a cascade of events really affecting every organ system within the body. And that can lead to cardiotoxicity, neurotoxicity, coagulopathy and DIC, vascular leak. And we do see severe cases of ARDS. It develops severe. Capillary leak syndrome leading to ARDS. And so it progresses throughout as the cytokines become higher and more activated. And so the hallmark features are really fever, hypotension and hypoxemia, which really affects the grading system now. And you saw this picture earlier, but it just affects all organs throughout the body. The risk factors for CRS that we've identified is the high disease burden and the high infusional dose, so a high number of cells that are infused. This is where really having a collaborative approach with your oncologist is important to know what are the number of cells that were infused, where did they think their disease burden was. Fluid Darabin containing lymphodepletion, so in that kind of conditioning regimen prior to infusion of cells, we identified that fluid Darabin can increase the risk of CRS. And concurrent infectious illness, of course. This is a SIRS-like response. So if you already have an infection, then this will get worse. And early cytokine elevations. Some prevention strategies that are really under investigation are targeting and trying to prevent this from happening. So pretreatment during cytoreduction, meaning giving tocilizumab early. Inverse dose adjustment by disease burden, so lowering the number of infused cells if you have a high disease burden. Fractionated dosing schemes and prophylactic anticytokine therapy. Here is the updated grading system from the American Society for Transplantation and Cellular Therapy. And it really focuses on the fever, hypotension and hypoxemia. And so you cannot have CRS without having fever. So fever always clues you in that there may be CRS going on. It may not be CRS, but you certainly can't have CRS without fever. And it progresses in severity here. This is really an algorithm that our group has looked at for treatment. And Ann's going to talk more about the specific treatment with use of anticytokine therapies. But really the main thing I want to point out here is that it really takes very close monitoring of these patients, even when they start to develop grade 1 CRS, which may just be fever. As they progress, early use of, or early utilization of the ICU services is encouraged. And transfer to the ICU is really paramount. These patients can decompensate incredibly quickly. It seems much faster than any of our patients with just frank sepsis. So really the best practices is making sure that you have written guidelines for complications, close observation, early ICU admission. And then you must rule out alternative diagnoses, most importantly sepsis. So looking at that, so looking at sepsis, is it CRS or is it sepsis? They present very similarly. You have kind of a cytokine storm with sepsis in general. And so it's difficult to understand if it's sepsis or not. And so treating for sepsis with empiric antibiotics is really paramount to treating these patients. Because we do know that from some of these studies that infections occur between the early days from 0 to 90 when they looked at a number of patients who were in a phase 1, 2 study. 80% of the patients occurred within 10 days after infusion. And as you remember, the first 1 to 14 days is when you see CRS. So this is at the same time that you're seeing CRS that you may have severe infection. 41% were severe. 44% were life-threatening or fatal infections. And so looking at the infections, 24 were bacterial, 13 viral, and 6 were invasive fungal infections. And so that's one thing you want to not miss as an invasive fungal infection as well. And here is another study looking at cytokine release syndrome grade as a predictive marker for infections. They identified 53 patients with relapsed BALL who received CAR T therapy. And 42% experienced 26 infections within the first 30 days. 17 bacterial, 4 fungal, and a few viral. And the CRS grade 3 or higher was independently associated with an increased risk of subsequent infection. And 6% died from infection-related cause. So best practices, again, treatment of respiratory insufficiency could be due to non-cardiogenic pulmonary edema. Early antibiotics, intubation, mechanical ventilation, BAL to exclude infection, lung protective ventilator strategies are all important. So managing these patients as we would any type of ICU patient is really important and not just focusing on the CAR T. Availability, though, of IL-6 inhibitors is necessary in order to treat these patients that Anne's going to focus a little bit more on soon. And then reevaluating these patients continually is also paramount and having the multidisciplinary discussion with the oncologist. Moving on to neurotoxicity, about 30 to 40% of these patients can have severe neurotoxicity. And this can be very disabling for patients and can have some long-term consequences. It's usually reversible but, again, can be life-threatening. And there have been fatal cases of patients who've developed cerebral edema and herniation. It usually occurs within the first eight weeks but can occur up to 10 weeks. The time of onset is about four to six days. And the median duration of the neurotoxicity is about two weeks, which is a long time for a patient to be encephalopathic. The symptoms really can range from just tremors. One of the big things that we start to see in the beginning is dysgraphia. So part of the assessment of these patients is actually handwriting. Because as their handwriting starts to go down, that is an early symptom that they're developing neurotoxicity. Mild aphasia, confusion, and that can progress to things more severe like status epilepticus and cerebral edema. The EEG typically shows diffuse slowing but can identify clinical and subclinical seizures. MRI can show some neurologic signs with a T2 flare hyperintensities in about 30% of patients. And we do utilize MRI in almost all of our patients who present with neurotoxicity. There's really two main forms of neurotoxicity. One is the acute form that occurs concurrently with CRS. And that is managed differently than the delayed or kind of idiosyncratic form that it can occur days to weeks later that does not occur concurrently with CRS. And I like to think of them as one is really related to the CRS part with the cytokine storm. And then the delayed really looks more like a leukoencephalopathy than anything else. And here is just another schematic of what happens. It's the same concept as what happens with CRS. Although we know that it actually can cross a blood-brain barrier. So your CAR T cells have been identified within the blood-brain barrier. Here's a nice study from Lee and colleagues and Jacoby and colleagues looking at identification of the CAR Ts within the brain. And so risk factors for neurotoxicity, older age and comorbidities, concomitant infection. It's disease related. So ALL has more neurotoxicity than diffuse large B cell lymphoma. The tumor burden. Again, treatment dose. There's certain CAR T characteristics. So which specific antibodies are being used can increase the risk of CAR T and the type of lymphodepletion. And then prior severe CRS. There's thought that potentially the use of tocilizumab may actually increase the incidence of neurotoxicity. And that's something that's relatively debated among colleagues. But the thought is that as you're binding the IL-6, you're actually increasing potential levels throughout the blood-brain barrier. And that may increase neurotoxicity. Here's the grading system. So it's based upon an ICE score, which I'll show you here in a second, that the nurse really assesses at the bedside on a Q8 basis. And then looking at the depressed level of consciousness, seizure, motor findings. And then once you develop into elevated ICP and cerebral edema. And here is really the ICE score. And they look at orientation, naming, following commands. As I mentioned, handwriting, which is different than we typically see in any of our encephalopathic patients. And then attention. So as their attention level decreases, that's a sign of neurotoxicity. Really what I wanted to focus on here, this is a kind of algorithm that we utilize as far as treatment's concerned. But it's using frequent neurologic exam, early use of imaging, considering seizure prophylaxis. And that's something to discuss with the oncologist and your neurologist. And then in grade two, really thinking about a lumbar puncture if there's no contraindication. Unfortunately, most of our patients are thermocytopenic and are unable to have a lumbar puncture performed. And then our early transfer to the ICU when they start to develop grade three. And grade four, management of cerebral edema and status epilepticus per your institution guidelines. So meeting early, I think if you're starting a CAR T program with the neurologists and neurosurgeons, is also very important from a multidisciplinary level. Management of ICP is really utilizing all the forms that we're used to. So trying to decrease cerebral edema. And when we look at safe delivery of CAR T, this is really just looking at how can we approach these patients from a multi-D level. And I think every talk has mentioned that today. And I know we'll go into more detail with Christina's talk as well. But it's, we need to have the experts at the bedside who use CAR T on a regular basis to help us with management. So to kind of conclude, no fever is no CRS. Sepsis is very common and needs to be treated. Neurotoxicity really has two types. One that's related to CRS and one that's caused by T cell expansion, that leukoencephalopathy. And then really considering early ICU admission. And thank you. Thank you very much. Our next speaker will be Dr. Anne-Raine Brown from the University of Texas MD Anderson Center. Who will be talking about the treatment of toxicities of immune effector cell therapy. Thank you for the invitation. And thanks for the introduction, David. So today I'll be kind of expanding on CAR T cell therapy. Specifically talking about the treatment of toxicities. I have no potential conflicts of interest. But I did want to mention that I'm an active and contributing member of the CAR TOX program and work group at MD Anderson and a contributor to our algorithm. If you guys do have an interest in app-based management in the ICU, there are two applications available. One by the ASTCT, the American Society of Transplant and Cellular Therapy. That really walks you through how to grade these toxicities that Colleen just focused on. And then we have a specific CAR TOX app that adds on the toxicity management. And there are institution specific guidelines. But ideally the ASTCT is also going to add on treatment shortly when they develop their treatment guidelines. So today I'm going to talk about applying treatment recommendations for cytokine release syndrome based on the patient's grade. And also treatment for ICANs. So as we've kind of mentioned today, severe and life threatening CAR T cell toxicities, including both CRS and ICANs, require urgent treatment and transfer to the ICU to prevent fatal outcomes. Both can be treatable if they are identified early. And treatment should be tailored based on the severity and grade. And we need to be able to identify known targets and understand the pathophysiology behind the toxicities so that we can identify what targeted agents we can use. So we've talked a little bit about it today. But I'm going to delve into the diagnostic markers that we use to target different therapies for both CRS and ICANs. So going back to the mechanism by which CAR T cell activation occurs. Once CAR T cells are activated, we get release of TNF alpha and interferon gamma. And as Colleen mentioned, really it's that in addition to the further activation of macrophages and monocytes, which release further cytokines, and a large amount of IL-6 and IL-10. There have been several studies that have associated with the severity of CRS with levels of IL-6. So Maud and colleagues in one of the pivotal trials for the approval of tesogen laclusol were able to correlate the level of IL-6 levels and the severity of CRS. In addition, colleagues at UPenn were able to associate elevated levels of IL-6 with severity of CRS, treat pediatric patients with tocilizumab, and see rapid resolution of their cytokine release syndrome. In that same trial, we were able to see a correlation between CRP elevation, ferritin elevation, interferon gamma, and also soluble IL-2 levels as far as correlation with severity of CRS. So in these patients, when you have these labs available and you see elevated levels and can trend them, they can kind of be predictors for patients that we need to treat and transfer early to the ICU. Looking at ICANs, there have been a couple of studies, particularly in the Zuma 1 study, that showed specific biomarkers that are specific for ICANs and not CRS, including IL-2, GMCSF, and also ferritin. So those were all correlated with higher peak levels in patients with more severe grades, so grade 3 and greater ICANs. So again, these are markers that we may be able to use in the future to predict patients with more severe disease. We've also been able to see that these cytokine levels not only correlate with severity of grade, but also ICU level of care. So patients that had higher peak levels of interferon gamma, IL-6, ferritin, and CRP all had increased incidences of ICU admission. For those institutions that don't have cytokine availability, immediate availability in their lab, CRP has also been shown to correlate well with peak IL-6 levels. So you can see here that as peak IL-6 levels rise, it correlates well with peak CRP levels. And then as the patient clinically improves, you will also see a timely correlation in the decrease of CRP. So now that we have an understanding of the different cytokines that we may be able to target, let's talk about some of the specific anticytokine therapy. So as we've kind of mentioned, IL-6 is one of the major cytokines that's released when CAR T-cells are activated. And in a mouse study, or a couple of mouse studies, they've shown that IL-6 and IL-1 levels are released upon CAR T-cell activation. It's thought that IL-1 release actually precedes the release of IL-6. And in this study, they were able to use an IL-1 antagonist called anakinra to target IL-1 and blockade of that actually decreased the amount of further release of IL-6. So we have two available agents to block IL-6, tocilizumab, as we've mentioned quite a bit today, and also sultuximab. Our IL-1 antagonist is anakinra. So we'll talk about it a little bit more, but tocilizumab is our mainstay of therapy. It's the only agent that's FDA approved for the treatment of cytokine release syndrome associated with CAR T-cell therapy. We use both sultuximab and anakinra off-label for the use of treatment of CRS and ICANs. There has been some debate in the literature and also in our clinical practice about the role of sultuximab and some theoretical advantage that it binds to both the IL-6 receptor and also soluble IL-6. So when you have receptor bound IL-6 blockade with tocilizumab, there's a theoretical increase in circulating IL-6 because it prevents IL-6 receptor bound, IL-6 to kind of disintegrate into the peripheral tissue. So as Colleen mentioned, there's a theoretical thought that it can traffic into the, cause trafficking of IL-6 into the CNS. So with sultuximab, there's a theoretical thought that it can prevent that trafficking of IL-6 into the CNS. We have not really seen any differences in the effects of sultuximab and it's also much more costly and less data and not FDA approved for the treatment. So for that reason, tocilizumab remains front line. Anakinra is an additional agent that will antagonize IL-1 and as I mentioned, we have a few mouse studies but no in human clinical trials to demonstrate the effectiveness of blocking IL-1 and the progression of CRS. But it's definitely something that we reserve in patients that are refractory. In patients that are not having improvement with IL-6 blockade alone with CRS, because of the plethora of cytokines and chemokines that are involved with the pathogenesis of CAR T-cell related toxicities, we can utilize corticosteroids for their global suppression of the inflammatory process. There is a theoretical idea that they do also suppress T-cell function. So for that reason, they've been avoided or kind of, clinicians have been worried about utilizing them in CAR T-cell patients for fear that they would suppress the activity of the CAR T-cells. There have been a few studies, particularly post hoc analyses that have looked at the response rates and the effect of complete response or overall response rates in patients that have received both IL-6 blockade and also corticosteroids. So does blunting of these cytokines affect the patient's response? And in post hoc analysis of the Zuma-1 study, they were actually able to show that both patients that received tocilizumab and glucocorticoids had no difference in their objective response rates. In addition, there was a safety expansion cohort of that same Zuma-1 study, and they looked at giving patients earlier corticosteroids. So when we started doing this five or six years ago, we put a contraindication to corticosteroids on all patients. We had to have a major discussion of when we were going to start steroids in patients that started exhibiting toxicities, but we actually started seeing that earlier we used steroids, the less severe or progression we saw in patients. So this study looked at evaluating earlier use, and they gave patients started steroids in patients with either grade 1 ICANs or grade 2 CRS, and they actually saw less progression to grade 3 neurotoxicity and also grade 3 CRS. So you'll see here 0% of patients progressed to grade 3 CRS that received early corticosteroids, and only 10% grade 3 neurotoxicity. So if you remember Colleen mentioning those usual rates of toxicities to grade 3 and grade 4, they're usually more around the 30 to 50% mark. So markedly less toxicities in patients that were given early steroids. This is just a schematic of all of the different characteristics of the main pivotal trials that have been studied in CAR T-cells to date, and the two that I've highlighted are real-world data. So basically after we've had these, both Axi-cell and T-cell go on the market, and what I hope to demonstrate here is that you see that patients are experiencing lower-grade toxicities, and that's probably the result of earlier and increased use of both tocilizumab and corticosteroids. So you can see compared to the Zuma 1, Eliana, and Juliet studies, we have a marked increase in the use of corticosteroids and tocilizumab. And this has just been basically dispelling the concerns that by giving some of these blockades for cytokine therapy, that we may blunt the response and the overall response of the CAR T-cell response in these patients. In addition, you can see kind of the same trends in ICAN toxicity treatment, but we have also seen the increase in tocilizumab and corticosteroids in these patients. But you will see that all of the different grades of ICANs vary in these studies, and as Colleen mentioned, as we've progressed through these clinical trials, we've had different grading systems depending on what institution the studies were performed at. We've also seen different practices and toxicities associated with the different products. So Axi-cell has an increased proclivity to ICANs versus tisaginoclusal has lower rates of ICANs, so it makes it hard to compare all of them. So here's just a summary of the different agents that we have to treat CRS and ICANs. I've talked about tocilizumab and sultuxumab as IL-6 receptor antagonists and anakinra as an IL-1 antagonist. We also have agents that we may use in refractory patients. So there's been a few patients that have received cyclophosphamide to blunt the immune response, also a couple case reports of ATG. And then depending on the product that you may have or see at your institution, there are some products that have safety switches which are manufactured or designed into the actual CAR T-cell so that we can infuse things like ICASPase 9 or remiducid to turn off the CAR T-cell production. And this is going to involve a major discussion with the oncology team and the ICU team to decide is the patient progressing to such a severe point or a life-threatening toxicity where it's worth foregoing the effects of the CAR T-cells and turning off that therapy to save their life. So the ICU management over the last five years has certainly been a moving target. As we gain more comfort and data with treating these toxicities, we've kind of changed our practices. As you've seen with the studies and then the real-world data, we've increased our comfort level with using some of these immunosuppressive agents to treat toxicities. And that was our comfort level and kind of increased awareness was really initiated out of several deaths that resulted from several of the trials. So the initial five deaths that occurred in the ROCKET-AF study with cerebral edema actually resulted in that trial being halted and that drug being pulled off the market. And then, but it's not specific just to that study in leukemia patients. So we've had deaths related to HLH, cerebral edema, CRS, and all of the products, so T-Cig and Leuclusal, Axe-C-Cell, and some of the other experimental products. And so for that reason, we really have encouraged aggressive early communication with the ICU team, with our merit teams to go assess those patients on the floor. And we had initially been admitting patients with more readily kind of attention to the ICU at around a 50% rate, particularly at MD Anderson. Now, we're at about a 20% rate of ICU admission as we've become more comfortable and also we're treating these patients earlier and not seeing such severe toxicities. The criteria for ICU admission varies pretty widely across institution, but kind of as a general statement, grade three and four toxicities should be managed in the ICU. So specifically talking about cytokine release syndrome and thinking about the cytokine targets that I've mentioned, we're going to take a targeted approach and grade the patient and then rule out any other causes of cytokine release syndrome. As you are aware, fever, hypotension, hypoxia can arise from lots of different differentials that can affect the patient, and so we have to work up the patient and rule out some of those other causes and treat the patient empirically as we need to. So there's lots of different things that can present like cytokine release syndrome. In addition to pneumonia, neutropenic sepsis, those are all going to present like CRS, so we have to empirically start antibiotics and think about giving patients tocilizumab or corticosteroids adjunctively with those therapies. There are also several on-target off-tumor toxicities that can occur, so where the CAR T-cell therapies may detect healthy tissues and cause acute kidney injury, liver failure, and lots, a plethora of other toxicities associated with the CAR T-cells. So as Colleen mentioned, our management really correlates with the grading. So if a patient presents with fever, we're going to monitor them unless they have persistent fever for greater than three days. At that point, you can consider blocking IL-6 with tocilizumab. If they have persistent fever, supportive care is always going to be combined in these therapies, so giving the patient acetaminophen, doing cultures, ruling out infection, and giving them fluids as needed. And just as a disclaimer, all of these treatment recommendations are our specific guidelines at MD Anderson. We are still awaiting the American Society of Transplant and Cellular Therapies recommendations, which I presume are going to be pretty similar to these recommendations. Grade 1 does not include any hypotension or hypoxia, so fever alone. Once the patient begins to have any hemodynamic compromise or requirements of oxygen, that's going to necessitate automatic administration of tocilizumab and consideration of dexamethasone. This is controversial, and it's based on some of those early studies that are looking at earlier administration of corticosteroids to prevent further progression to grade 3 and 4 toxicities. So, it really involves a discussion with the ICU and oncologic team to decide whether or not the patient should receive steroids. And that may be based off of risk factors that the patient has. So, do they have a high disease burden? Did they get a high cell count in their CAR T-cell infusion? For grade 3, we're going to administer tocilizumab if they have not already received it. And at MD Anderson, we've actually taken a different approach than what the ASTCT guidelines say. So, their recommendations are based on the number of vasopressors and exclude vasopressin as a vasopressor. We just look at the number of vasopressors, but also the number of norepinephrine equivalents. So, as we know, the patients that are received greater than 15 mics per minute norepinephrine equivalents have an increased mortality in the VAST trial and a couple of other studies. So, in patients that are on higher doses of vasopressors and not just the number of vasopressors, we like to do higher doses of corticosteroids because that may signify that they're progressing into a grade 4 picture. In addition, patients that are hypoxic should also receive tocilizumab plus the combination of dexamethasone. And at this point, all grade 3 patients at MD Anderson we recommend transfer to the ICU. Moving on to grade 4, this would be patients that are requiring multiple vasopressors or requiring invasive mechanical ventilation or BiPAP. And these patients should all receive tocilizumab and also high-dose methylprednisolone. So we switch from high-dose decadron to a gram per day of methylprednisolone in divided doses depending on patient tolerance. And at this point, this is when you should be having continual multiple times a day talks with the oncology team to decide about refractory treatments like cyclophosphamide, possibly pulling an anikenra for that IL-1 antagonism, and deciding if there's any safety switches for these patients. So in summary, CRS management is going to vary by institution until we see what the ASTCT recommendations are following. And really, you should base it on clinical parameters. There are not laboratory parameters. We can use cytokine panels if they're available at your institution, look at CRP correlation for severity of illness. But you really want to look at hypoxia, hypotension, and the presence of fever. Moving on to neurotoxicity management, we use the same step-based approach. And you rule out any other attributable causes. So obviously, decreased level of consciousness, seizures can be caused by a plethora of things in an oncologic patient. But the one defining characteristic of ICANs or CAR-T cell-related neurotoxicity is the global aphasia and the timing that a patient may experience these neurotoxicity syndrome. So it's important to work up the patient, get a CT scan when they come into the ICU, EEG, to rule out nonconvulsive status epilepticus, and get your neurologic colleagues involved as well. So as Colleen mentioned, we use the iSCORE to grade ICANs and look at their level of consciousness for grade 1. This is the point where we're going to give upfront corticosteroids to patients that experience any neurotoxicity, so a one-time dose and then reassessing. And we really don't want to give tocilizumab unless they have associated CRS. So if they have an accompanying fever or you're having to give them fluids to manage their blood pressure, you can consider tocilizumab. But there have been some theoretical concerns about giving tocilizumab in patients that have neurotoxicity alone and the worsening of neurotoxicity by allowing IL-6 to traffic into the CNS. So that's something that you really have to look at carefully when you're administering tocilizumab in neurotoxicity patients. Once they progress to grade 2, we're going to start scheduled corticosteroids. And again, if they have concurrent CRS, administering tocilizumab. For grade 3, if they are just having depressed level of consciousness, no one's home, global aphasia, we increase the steroid medications to Q6. And if they have persistent aphasia or an ICE score of less than 3, then we may increase the dexamethasone to 20 milligrams every 6 hours. And all of these regimens are going to be tapered as you see resolution of the patient's symptoms. If they have accompanying seizures or cerebral edema, we are going to increase steroids and also manage those findings as you would for your institutional guidelines. So transferring to the ICU, treating the seizures. And there's not a, well, I'll talk about that in a second. So grade 4 would include an ICE score of 0, so the patient's unarousable or abundant, life-threatening or repetitive seizures. Any deep or focal motor weakness would be automatic grade 4. And they're going to be on high-dose corticosteroids. And then the findings of diffuse cerebral edema and an increased ICP would also be a sign of grade 4 ICANs and necessitate high-dose corticosteroids. I just have the seizure management here for you to look at. But every institution is going to treat seizures differently. There's not one particular antiepileptic drug that's recommended by one institution. We use Keppra as our maintenance medication and also prophylactically in these patients that are at high risk for neurotoxicity. But some institutions may use Vempak. Or depending on allergies or contraindications, patients may be on other antiepileptic drugs. If they have persistence, we start phenobarbital at our institution. But you have to watch out a lot for drug interactions, particularly with the antifungal agents that these patients have to be on to prevent increased risk of fungal infections. In addition, here's our algorithm for the management of ICP, which involves high-dose steroids and hyperosmolar therapy. So in summary, all of these toxicities come at a expense for the patient. We have gotten a lot better with treating these toxicities early and preventing progression to grade 4 toxicities. But as we continue to see different products, it's important to recognize that CD19-targeted therapies may function very differently than, say, CD22. So we may see much less toxicities with some other products than we may see to the point where we're doing increased infusions of these on the outpatient setting and we're having to monitor these patients for admission to the ICU or into the hospital in general. But the mainstay currently is tocilizumab for IL-6 blockade and corticosteroids for global suppression. And we may see that more targeted therapies emerge as frontline therapy as we learn more about the progression and pathogenesis of this disease. And I'll just stress, as we've all stressed, that it really involves careful communication and collaboration with the oncology teams, infectious diseases, neurology teams, and also our critical care teams to manage these patients effectively. Thank you. All right. Thank you very much. For our last presenter today is Dr. Cristina Gutierrez, who will be talking about uncommon toxicities and other considerations of immune effector cell therapy in the ICU. Thank you. So after that complete presentation by both Colleen and Anne, I'm going to talk a little bit about some of the other toxicities you'll be seeing in the ICU but are not as common. And I also want to touch base a little bit about, as intensivists, you know, what are the things you have to be looking for whenever they're bringing a car or an immune effector cell program to your institution. So I have no conflicts of interest. And we're going to review the uncommon toxicities. We'll discuss the impact of a CAR or immune effector cell program in your institution and in your ICU. And I'll somehow touch a little bit on the gaps that we have in the literature right now when it comes to critically ill CAR T cell patients. The majority of the talk, I'll be probably talking about data on CAR T cell products, mostly CD19. And once in a while we'll talk about some other immune effector cells. So as Colleen mentioned, probably the most important one that you're going to be dealing with are going to be infections. And when you think about these patients that are receiving CAR cells, they have multiple risk factors to develop sepsis and severe infections. First of all, these are patients that have been receiving multiple lines of therapy. They have a very suppressed bone marrow. And they're going to be cytopenic for a very prolonged period of time once you give them induction chemotherapy. Not only that, when you think about the long term, a lot of these patients are going to be developing B cell aplasia. And up to 67% of the patients are found to have hypogammaglobulinemia. So all of these things will put them at a higher risk than any other patients for infection. The incidence, you know, has been reported to be as high as 42%. And up to 10% of these patients end up in the ICU with severe infections. As Colleen mentioned, you know, the most common ones are going to be bacterial infections. And you're just going to have your bread and butter bacterial infections that you're going to be seeing in immunocompromised patients. You know, your gram positives, gram negatives, multidrug resistance, stenotrophomonas, C. diff have also been described in this patient population. When it comes to viral infections, you know, CMV and HSV reactivation is relatively common. And when you look at your fungal infections, you're not only talking about aspergillosis, but you're also going to have a high incidence of candidemia on these patients. You have multiple risk factors for it. So it's something to keep in the back of your mind. As these guys mentioned earlier, you know, usually the infections, you're going to see them between the, usually in the first 28 days, which is usually when the patients are still hospitalized. But you can see these infectious complications as late as 100 days post-card T-cell therapy. And taking this into account, a lot of the institutions have come up with their own guidelines of giving PCP, HSV, antimicrobial, and antifungal prophylaxis. And all of these are probably based on literature for stem cell transplant patients. And while we're all using these, you know, there's probably not real data sort of looking at which are the guidelines that are probably more effective for this patient population. So more studies are needed in this area. Now on the two bigger papers that were published on infections in this population in 2018, some of the risk factors that they described were patients with ALL, those that had received multiple lines of therapy, and those with high-dose cell dosing were at a higher risk of developing infections. What was very interesting about both of those publications is that they actually found that those patients that developed rate 3 and more CRS were at a higher risk of infections, not only bloodstream infections, but also any other type of infection. So and also what is interesting is that this was also not associated to the degree of corticosteroids, that were used on this patient. So it's almost like if this inflammatory process somehow makes these patients prone to an increased risk of infection. Now one of the common questions that we get whenever we give these presentations is, you know what, CRS is just like sepsis. How can we actually differentiate one from the other? And the answer is there's no way. You know, we sort of talked a little bit about measuring CRP, measuring ferritin on these patients, but as you know, these are all very nonspecific markers. One of the things that we used to think is that probably the elevation of all of these cytokines that these guys were talking about, interferon gamma, IL-6, IL-10, were probably very specific for CRS. But when you look at the data that has been published, when they looked at patients with infection, this one's in red, and those without a infection, independent of the grade of CRS, there was no difference on the level of cytokines. So these are probably markers that we still can't use as predictors or to help you diagnose whether or not if your patient is infected or if they have CRS. Another complication that is very uncommon, however, it has been reported with pretty much all of the products is HLH. The incidence is reported to be less than 1%. And as you all know, you know, HLH is already a very difficult syndrome to diagnose and to actually treat. And when you put that in the context of CRS, it makes it even more complicated. When you think about the pathophysiology of both HLH and CRS, it's fairly similar. When you think about it, it's the sort of severe inflammatory process that is leading to multi-organ failure. And that happens in both of these cases. When it comes to the clinical features, when you think about a lot of the clinical features that we use for the diagnosis of HLH, splenomegaly, hepatomegaly, elevation of ferritin, fever, multi-organ failure, all of your patients with CRS are going to be having this, which again makes the diagnosis very difficult for these patients. So the only thing that might actually leave you with is whether or not if your bone marrow and your levels of CD25 and serum are going to be either elevator or if you're going to be seeing hemophagocytosis on your biopsies. However, as you know, you don't always see these positive in patients with HLH. So again, it's something that is very difficult to diagnose. Now the other question that you have to think about is whether or not if they're really – if they are really different entities. And there's an idea that maybe HLH in this patient population is probably just a spectrum of very severe CRS or refractory CRS. You know, in this paper published this year, Hashmi and their group, what they did is they actually looked at some of the cytokines that you see elevated in HLH. And they found that they're also elevated in patients with grade 3 and grade 4 CRS. So that makes you think that maybe HLH is just a spectrum of just very severe CRS in this patient population. And then the next question you might have is how do you treat these patients? And we don't really know. You know, at this point we just treat them as patients who have very refractory HLH. You know, in our institution we sort of say that if after 48 hours your patients are not really responding to therapy, you really think they have HLH, maybe you can consider initiating a topocyte. But there's really no data supporting these decisions. Other reported complications that we've seen in the literature, you know, some of these patients with neurotoxicity end up having both hemorrhagic and ischemic strokes at the same time. Tumor license syndrome has also been described on those patients with high tumor burden. Myopathy and neuropathies we're seeing more and more in our patient population, especially those that you're treating in the ICU and that are requiring high dose steroids. However, we need a little bit more data to sort of see which are the patients that are high risk for this. Something that has been interesting is those patients that develop neurotoxicity, about 50 to 60% are developing cognitive difficulty, anxiety, and depression in the long term, which definitely puts them at a higher risk of delirium later on if they get admitted to your ICU. On target of tumor toxicities, as Anne-Marie was talking about, have also been described. And the question is whether or not, if now that we're going to be starting to use allogenic immune effector cells, whether or not if some of these patients are going to be developing graft versus host disease in the long term. So now here comes what's important for you as an intensivist. What do you need to know about, you know, if your oncologist comes up to you and tells you I'm going to start this program? And one of the things that we see is that a lot of people say, well, what's the point of me actually worrying about CAR T cells? I'm never really going to be seeing this. And this is where I tell you, you know, you are probably going to start seeing this. We already have a two-year data on these patients, and we see that their survival is up to 50%. And when you think about it, that's really high. These are patients that were already being considered for hospice, patients that had no treatment therapies available. And when you think about this patient population in general, you know, any treatment after two years, their survival is only 20%. So this is very striking. And this is the future in immunofactor cell therapy. These are all of the products that are being studied out there. So they are coming. They're all coming down the pipeline. We probably have two more products that are going to be FDA approved relatively soon. So you will be seeing this in your institutions. So let's say your oncologist comes up to you, and they tell you, you know, I want to start this program. And your first thought is, why do I even care as an intensivist? And this is when I tell you it's extremely important as an intensivist to be involved early. You want to be a part of this program. You know, education is going to be extremely important, not only throughout the hospital, but also in your ICU. These patients present clinically very, very differently to everything that we're sort of used to. Their neurotoxicity is extremely different. You know, the CRS, it's another type of presentation. So people need to be aware of this. You also want to know what resources you're going to be needing in your ICU, what volume of patients you should be expecting in your unit. You want to be a part of the protocols in managing some of these patients and some of the severe complications. And you want to make sure that you recognize these patients early on the floor and bring them in. So as your oncologist starts telling you which are the patients that you're going to be bringing, they're going to be bringing, it's probably going to blow your mind. They're going to be talking about patients with hematological malignancy, which you already know have a very high mortality, right? This is the patient you don't want in your unit. Then they're going to be telling you, oh, but they have relapsed refractory disease. And you're like, what are you talking about? This patient has 100% mortality in my ICU. Why would I even bring this patient? And this is probably when we have to start thinking that maybe it's time to start rethinking whether or not if some of these patients with relapsed refractory disease are going to start needing ICU admission. You know, we had some of these concerns in our institution. And what we did is we looked at some of our CAR T-cell data. We looked at all the lymphoma patients that were admitted after axi-cell approval. And we compared those patients with lymphoma treated with CAR T-cell therapy versus those that were not treated with CAR T-cell therapy. And what we found was actually striking. We saw that the ICU mortality of our CAR T-cell patients was extremely low, just 5%. While it was 31% when it came to those patients not treated with CAR T-cells. Not only that, if we match that to the admission SOFA score and the maximum SOFA score during ICU admission, we still saw such a low mortality. Not only that, we saw that the hospital mortality, 30-day mortality, 60-day mortality was still extremely low. And not only that, but the majority of these patients were going home. So these are patients that you're treating in the ICU aggressively. They're extremely sick and they get to go home and maybe survive and live a good life. So this is when you have to start thinking, well, maybe all of the risk factors that have been ingrained in my brain of who are the patients that will die in the ICU are probably not good predictors in this patient population. And you have to think that a lot of this is going to be reversible and that your patient will do well and they will go home. So they survive. And then your next question is, well, what resources am I going to need to treat these patients in the ICU? I've heard that they get extremely sick. Will I have the money to do this? So we decided to look also at what were the resources that these patients were utilizing in the ICU. And surprisingly, we saw that the ICU length of stay was no different for our CAR T-cell patients. ICU readmission was also no different for this patient population. And not only that, but we also saw, you know, the amount of tests that these patients were using, procedures were no different. They were using probably less vasopressors, less use of mechanical ventilation, high flow and BiPAP. And probably the only thing that was higher was the use of EEG and LPs, which makes sense when you think about the high incidence of neurotoxicity on this patient population. When it comes to the rate of ICU admission, which is something you want to know, so when you compare it to the non-CAR T-cell patients, lymphoma patients, definitely the ICU admission rates were higher in our study, 50% versus 21%. But as Anne-Marie was saying, you know, this is probably the jump that you see initially. And as people get more comfortable with treating these patients, you'll probably start seeing that there's a decrease in ICU admission rates. And we have it right now at around 20% for all immunofactor cell therapy in our institution. Now when you look at the data, 30% to 40% of patients in all of the studies have been admitted to the ICU. And when you think about the ASTCT grading, which is the one that everybody is using, you'd say, well, it's very easy. Anybody with grade 3 and 4 CRS should be admitted, which is anybody with pressors, mechanical ventilation, so between 7% to 20% of patients. When you look at neurotoxicity, yes, it should be just grade 3 and grade 4, somebody who can't protect their airway, the patient that is seizing, the patient that has cerebral edema. So that brings it to about 40% of your patients. But there's a large variability between the products and how they're going to manifest and the degree of toxicity that you're going to be observing in this patient. It has to do whether or not if you're doing a T cell receptor versus a CAR, you know what they're targeting, the cost emulatory molecule, but whether if it's T cell and K cell, allogenic versus autologous. So there's going to be a large variability, and this is where it's important to talk to your oncologist so that you get a better idea of what to expect once the program starts. And there's also a big difference when you think about your studies versus real life, right? You'd look at all these studies. They're very well controlled. They choose very well their population. When you look at real life, we're treating extremely sick patients, patients that probably are going to get sicker than what you'll see in the studies. And this is why we have created the CAR ICU initiative. You know, we want to get a good idea of how these patients are being treated, you know, how sick they're getting in the ICU, what are their outcomes in real life when we treat these patients. We have included 12 centers within the U.S., and all of these are large centers that have been treating patients with CAR T cell therapy for some time. So as part of our initiative, you know, what we did is we surveyed 11 of these 12 centers. And when you look at ICU admission criteria, we were striked from what we actually found. We saw that as many as 73% of the centers are actually admitting patients that only have grade 1 and grade 2 toxicities. And this was the same when we came to neurotoxicity. Up to 81% of the centers are actually admitting low grade, grade 1 and grade 2 toxicities. So it all depends on the centers, the capabilities that you might actually have on the floor. So all of these things are things you have to keep in mind when the oncologist brings these treatments to your ICU. So yes, they tell you, you know, they've spoken to the right people, administration will give you all the money and everything you need to be able to treat these patients in your ICU. So you want to know whether or not if we have guidelines to treat this patient. And if you Google PubMed, how you treat CAR T cell therapy toxicities, you're going to find multiple recommendations, multiple papers. And we actually published our guidelines on how to manage the critically ill CAR T patients. All of these are very good papers, they're all based on the experiences of people that have been treating these patients for a prolonged period of time. But there's probably very little hard data to support some of these interventions. And this is something that we actually have to think about when we're treating these patients. And also there's a large area of studies that we could be doing on this patient population. So taking this into account, you know, when we were surveying these 11 centers, we wanted to see how these patients were being treated in the ICU. When we looked at the management of CRS and some of the support for neurotoxicity also within the ICU, we saw that there was a large variability on how these patients were being resuscitated, vasopressors that were chosen, inotropes that were being chosen. You know, the rates of mechanical ventilation and how these patients were managed whenever they had respiratory failure were pretty much the same as what is reported out there for oncological patients. And even the monitoring for brain edema and the management of cerebral edema, there was large variability within all of these centers. Not only that, but also when it came to the treatment specific for CRS and for neurotoxicity, there was also a very large variability. You know, the dosing and whether or not if we were using tocilizumab, how many doses also varied. The use of siltoxamab and anokinra also varied significantly. The doses of corticosteroids, when corticosteroids were started. And also rescue therapies. Those are the patients that we're going to be seeing in the ICU, the ones that really are not responding to corticosteroids or any of the other therapies. And we realized that a lot of hospitals are just using whatever they can think of to try to sort of suppress this inflammatory support. So all of this left us just sort of realizing that there's more questions than answers. There's a large area here that we could be studying and that we could actually sort of be improving the outcome of these patient population. Remember, these are patients that are going to get better. And these are patients that are actually going to be able to go home. So we want to make sure that whatever we're offering those patients is adequate care. So in conclusion, you know, there's less common complications that you still have to keep in the back of your mind when you're admitting these patients to the ICU, such as HLH, sepsis, tumor lysis, and stroke. But due to their low incidence, you know, we need more collective data so that we can come up with clear guidelines and identify risk factors for some of these complications. The early involvement of the ICU team is of extreme importance, and this is when you guys should be definitely very proactive within your institution. It will definitely make a difference. And collaborative efforts such as the CAR-ICU initiative, you know, are needed to improve the care of this complex population. And I'd like to acknowledge, you know, the CAR TALKS committee at MD Anderson-Kanzen Center, and also all of the centers within the CAR-ICU initiative that are also members of the Oncognit. That's it. Thank you very much for that great presentation. At this point, I would like to invite our speakers up to the stage to answer any questions. And if you would like, please come up to the two microphones that are in the audience. Can you hear me? Okay, cool. I have a question specifically as it relates to ICANNs. I think during Anne-Raine's presentation, in treating ICANNs 3, I believe you utilized decadron, high-dose decadron, versus ICANNs 4, you used high-dose methylprednisolone. And I just wonder why there's that difference between using those two steroids. So there's not a lot of data, but it's thought that once you transition to a high grade of neurotoxicity, using methylprednisolone has a higher anti-inflammatory response. And giving such large doses of decadron that would be equivalent to solumedrol would be at the expense of a lot of more, I guess, side effects or intolerable for patients. So we use high-dose solumedrol instead of decadron in those patients. Hi. In my center, we seem to be reluctant to use TOSI, to pull the trigger on TOSI. And I think, you know, there's obviously this maybe inappropriate thought that TOSI is going to suppress the CAR product, and even more so with steroids. And the financial burden, of course, of TOSI is not insignificant. Do you see any trend possibly heading towards using steroids before TOSI, or any other options to, you know, because the cost really kind of inhibits people towards using it, which seems kind of silly compared to the cost of the CAR product itself. Anyone can answer. So I think that, you know, we know that tocilizumab is really one of the mainstays, along with steroids, of treatment of CRS. And so I think just urging the institution to relook at that, as you said, the cost of CAR-T is quite high. And so use of tocilizumab is really kind of inconsequential to the CAR-T product. But early use of steroids, I think, is also very important, as you mentioned. And there may be something with the early use of steroids that may offset a lot of the CRS, too. I think that we're still kind of learning when exactly to dose the steroids and tocilizumab. But once they start exhibiting, you know, grade 1, and particularly grade 2, I would certainly start steroids. And we have had data that there is not going to be any significant blunting effect of the CAR-T with steroids and with tocilizumab. That was kind of early on that there was concern that we would blunt the response of the CAR-T. You'll still continue to have anti-tumor effect after dosing with tocilizumab and with steroids. I don't know if there's anything else to add. Sorry. I would add that at our institution, I mean, obviously the FDA mandates that you have to sequester doses of tocilizumab, particularly for the patients that are on the FDA-approved products through the REMS program. But we've employed a couple of strategies where we cap doses or decide what weight we want to use for the patient for tocilizumab. So you can try and, you know, limit the cost from that perspective. But I think with it being the only FDA-approved product for the treatment of CRS, it kind of limits our kind of hesitancy to use that product. Again, compared to the cost of these therapies and the costs up front for these patients, it's hard to say we're not going to use it in those patients. Yeah. I think it's important to identify the risk factors for the patients that are more likely to develop, you know, increasing grade of CRS. So I'm not advocating that we should always try to prophylaxis everything. Since sepsis is a great mimicker of CRS and a quarter of the patients will have sepsis and not CRS among these patients, you might want to be careful just tossing in steroids too quickly. But there's no question that, you know, you should have Toc available, but you should be careful when you use it. So we know those who have certain constructs of CAR-T will be more likely to develop more severe CRS, tumor burden. I mean, it's really just understanding the risk factors and the patient profile and looking to see. We do a lot of cytokine studies on all our patients that get any of these immune drugs. So we have the advantage of looking at the IL-6, you know, quickly and we can determine, oh, this is a patient that might fit more of that category. But for those who don't do that, then you're really relying on clinical. And in that case, I'd be a little careful in without understanding the risk factors that would make more likely a patient to get Toc early and steroids early only because of the problem of sepsis being in the mix and you don't want to further immunosuppress patients and run the risk of more devastating infections, you know, if you just kind of treat everybody the same way. Thank you so much for hosting the session. I know that procalcitonin can be rarely elevated in situations of anaphylaxis, so it might be inconsistently useful. But has the role of procalcitonin been used in identifying CRS versus sepsis? The answer is no. No. I mean, it's probably something that we should be looking into. There's no reason why we shouldn't. It's probably a cheaper way to actually help. I think what we're seeing more and more is while we know that some of these inflammatory markers are elevated, we still don't know preemptively which are the ones that are actually going to help you determine whether or not that patient is going to be getting toxicities or not. In that right moment, it's very difficult, actually, to differentiate one thing from the other. So I think whatever tools you might have that could guide you with that treatment or diagnosis is definitely worth it. And definitely, procalcitonin should be one of those things that you should be looking into. But yeah, nobody has really looked into that yet. I wish I could share with you data, but that's under review right now. We did look into that, combining cytokine markers with procalcitonin. We also thought in the early going, when we were doing an early validation, IL-6 added to procalcitonin appeared to be carrying a very high sensitivity for the diagnosis of CRS as compared to just sepsis. But as we got more and more data, that distinction seemed to not be as clear. And so procalcitonin, while it's good for bacterial infection, we have seen patients who are very sick whose procalcitonin levels don't really go up as high. But the one thing that we found, and this is not related just specifically to immunotherapeutics, is that it's been always said that procalcitonin levels tend to not go as high if you're neutropenic. And it loses sensitivity from 80% to 60%. We did not find that. And as I said in the paper that's under review, we found that the levels of procalcitonin were just as high and predictive of bacterial bloodstream infection, even in patients that had very low white cell count. We're talking A and C less than 0.5. So I think procalcitonins have to be interpreted within the context of your patient population. And keep in mind that there are a lot of false positives with procalcitonin. So it should only be used to complement your clinical suspicion, your risk factors for infection, and whether or not it's going along with that. But if it doesn't fit, then you should not use procalcitonin alone to determine whether you're going to start antibiotics or not. Switching topics, a question about checkpoint inhibitors. And specifically, which patients would you consider re-challenging with checkpoint inhibitors? And concerns about subsequent radiation therapy for patients who have radiation pneumonitis? Well, usually they are re-dosed after leaving the ICU. But in general, the recommendation is that the patients remain on steroids until all these toxicities are resolved, whether it's pneumonitis, renal toxicity, liver toxicity, et cetera. And it could be reintroduced later on once the patient has stabilized, if there is a further need. Some patients may have complete remission of the disease. But I think that these type of decisions don't really fall in the purview of the intensivist. It's really when the patient becomes ambulatory back in society. Did you have any comments? As a pulmonologist, I see a number of these patients on the outpatient setting as well. And so if they've had grade 3 to 4 pneumonitis, just specifically talking about pneumonitis, but if they've had grade 3 or 4 pneumonitis, they do not get re-challenged at our institution. There have been some very select patients that kind of fall along like a grade 2 to grade 3 that we've re-challenged with low-dose steroids. Now, in immunotherapy, the steroids actually do blunt the response of the immunotherapy. And so this is definitely a discussion with the oncologist and in very select patients. And then as you mentioned with the radiation, previous exposure to radiation therapy does increase the risk of pneumonitis in these patients. And so, again, looking at your patient population and kind of what their previous risk factors are certainly play in a role into whether or not these patients would get re-challenged even with lower grades pneumonitis. And for patients who have been treated and who have had pneumonitis, do you ever consider radiation subsequently? Not that I'm aware. I honestly have to defer to the oncologist about like usually it's previous to the immunotherapy. I mean, and something that we're starting to observe is that they're using radiation concomitantly with some of these immunotherapies, including checkpoint inhibitors and also cell therapy. So that's maybe something that you might start seeing. It's usually very localized. And what they're hoping is that they're just going to increase the exposure of the antigen and also increase the inflammatory response. And so that might be a little bit of what you might be seeing in some of the centers. All right. I think we could squeeze in one more question. Yeah. Hi. Thank you for this interesting talk. I'm interested in knowing if at your institution or anywhere else, are you guys aware of anybody looking at the composition of CSF in these patients to give more data to this theory that we keep hearing about, tocilizumab versus ciltoximab and levels of IL-6 maybe in CSF and helping to give data to that theory? Under way. Yes. Anybody that gets a lumbar puncture gets a lot of beyond the usual studies that are done for care are getting a lot of analysis of a lot of these different cytokines in hopes that we could identify a profile that would allow us to select this drug versus another. So unfortunately, we don't have all the results in yet, but it's being looked at at least at our place and I'm sure at other places as well. And if you look at the data, there is data supporting that, you know, cytokines are elevated on these patients during neurotoxicity, so IL-6, IL-10, interferon gamma. And you also, as they were mentioning, you know, you see the CAR-T cells actually in the CSF. And, you know, depending on the level of the cytokine, I guess, it also correlates with the grading of your neurotoxicity. So that's what you'll see. All right. Thank you very much. One more round of applause for our awesome presenters today. Thank you.

CAR-T cell therapy

T cells

cancer cells

toxicities

cytokine release syndrome

CRS

immune effector cell-associated neurotoxicity syndrome

ICANS

tocilizumab

IL-6 receptor antagonist

neurologic symptoms

imaging

seizure prophylaxis

oncology

neurology