Thank you for the introduction. So, as mentioned, I will be today talking about the updates on FDA-approved CAR T-cell products and their toxicity profiles. And I have no relevant financial disclosures to make. So, as most of you might know, CAR T-cell therapy is a type of immune effector cells that are genetically engineered to express chimeric antigens or CARs. And those allow the ability to overcome the tumor's immune system and evade that. And as a result, they also launch a powerful immune response, which can produce quite significant toxicities. And while CAR T-cell therapies have produced pretty significant responses, they have the ability to produce significant toxicities that bring these patients to our ICUs and prompt aggressive management by our teams. And a few early deaths in the early clinical trials led to the prompting of the halt of one clinical trial and prompted a heightened awareness across the country and also escalation of care for these patients in our ICUs. And so, prescribing of the FDA products require both REMS oversight and clinicians should be highly trained and aware of the clinical guidelines that guide the treatments of these toxicities. So, two leading societies have published clinical guidelines, the American Society of Clinical Oncology and the American Society of Transplantation and Cellular Therapy. And ICU clinicians, in addition to our consultants in the ICU, should be familiar with these. So, beginning with the approval of tesogen laclusol in early 2017, there are now six products that are FDA approved. For a myriad of B-cell malignancies, including large B-cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia, and also most recently multiple myeloma. It should be noted that the guidelines and the grading that we will talk about in the treatments are primarily based on the approvals and our experience with the first three products that we saw in 2017 to 2019. So, unlike chemotherapy side effects and toxicities that are usually nonspecific and can cause permanent organ damage, many of the CAR T-cell toxicities that we see are usually on target and they're also reversible once the CAR T-cell cells are done expanding and eradicated. As CAR T-cells multiply, they can release a large amount of cytokines and they can ramp up our immune system. So, we see both cytokine release syndrome and a neurotoxicity syndrome known as ICANS. Both of these syndromes commonly bring our patients to the, these patients to the ICU. There are several proposed targets for the treatment of both cytokine release syndrome and ICANS, primarily directed at the pro-inflammatory cytokines released upon CAR T-cell activation. So, activation of macrophages secrete inflammatory cytokines which can ramp up our immune system resulting in both CRS and ICANS. Both of these, which again, bring our patients to the ICU. So, the release of these cytokines drive vascular leakage that can result in hypotension and further activation of this all is in an inflammatory loop and leads to multi-system organ failure. So, the mainstay of treatment is targeting both IL-6 and IL-1. So, primarily cytokine release syndrome is thought to be driven by IL-6. And so, our mainstay targeted treatment is Tocilizumab, which you guys are probably all familiar with through the COVID-19 pandemic. Similar to the CRS pathophysiology, ICANS seems to start with the production of pro-inflammatory cytokines and the activation of bystander immune cells, as well as macrophages, which can release both IL-1 and IL-6. And so, these inflammatory cytokines result in disruption of the blood-brain barrier and is thought also to result in accumulation of CAR T-cells in the CNS, which can result in neurotoxicity. And so, the mainstay of treatment for ICANS remains a global immune suppression with corticosteroids. But there is some emerging data for just targeting IL-1, which is used, which is targeted by Anakinra. So, now that we kind of understand the pathophysiology, let's talk about how to grade cytokine release syndrome and then ICANS. So, the most common symptoms of CRS are fever, hypotension, and hypoxia. Grade 1 CRS is attributed to fever alone. So, if you have fever and no signs of hypotension or hypoxia, that's automatically a grade 2 or higher. Patients that require mechanical ventilation or vasopressors are automatically going to be a grade 3 or 4, and those patients are going to be treated in our ICUs. As the syndrome evolves, you're going to have different organ systems that are affected, and this can progress to multi-organ system failure. It's important to note that with the ASTCT guideline updates, they only included fever, hypotension, and hypoxia in the grading of these patients. But it's important for clinicians to take into account other organ system failures that we see in these patients, such as liver and kidney disease, and be more aggressive in the treatments of these patients that also have these other deteriorations. So, once you have excluded any other causes for fever, hypotension, and hypoxia in these patients, and you can attribute it to cytokine release syndrome, you're going to look at mainly supportive care for these patients, so our general mechanical ventilation, hypotension management, as we would any of our septic shock patients, but also targeted therapies against IL-6 and global immune suppression with both tocilizumab and corticosteroids. So, grade 1, you're going to consider a dose of tocilizumab if they have persistent fever. Grade 2, add on corticosteroids if they have persistent hypoxia or hypotension. Grade 3, once they start requiring vasopressors or higher amounts of oxygen, you're going to schedule corticosteroids. And grade 4, be much more aggressive with the corticosteroid dose. Now, again, it's important to realize that if you look at the package inserts and the clinical trials for each of these specific products, they're going to have minute differences in the dosing of corticosteroids or how aggressive or early you may treat with tocilizumab. But at our institution, we've decided to make a global recommendation based on the grading. And again, you may have discussions with your oncologist team or your infectious disease team and make decisions about being more or less aggressive with the initiation of these therapies. The management of neurotoxicity follows the same approach. So, you're going to determine the grade of the ICANs and then follow the management algorithm. Again, it's important to discard any other causes for altered mental status when working up these patients. So, getting a CT scan, looking at their history, and making sure you can exclude other reasons. The grading of ICANs takes into account something called an ICE score. And that's meant to capture the most characteristic symptom of ICANs, which is a global aphasia. It asks the patient a number of different questions to try and capture that aphasia that happens predominantly in this syndrome. In addition to the ICE score, ICANs incorporates depressed level of consciousness, presence or absence of seizures, presence of motor findings, so deep focal motor weakness, and early signs of cerebral edema. If the patient is able to perform the ICE score and score well and also awaken spontaneously, that's a grade one. And predominantly, we're just going to watch that patient with supportive care. Grade two, if they don't score as well on the ICE score, they can't answer some of the questions or do the writing assessment, awaken only to voice, that's when you're going to consider corticosteroids in this patient. Once patients progress to grade three or four, again, should be transferred to the ICU and monitored aggressively, particularly for the prevention of progression to cerebral edema or being able to identify patients that may be presenting with non-convulsive status epilepticus. In both of these cases, you're going to schedule corticosteroids and escalate the dose as their syndrome progresses. Seizures and cerebral edema should be managed according to your local institutional guidelines based on standard of care, really no differences in the way we would treat those patients, though considering drug-drug interactions with some of our anti-epileptics. It's important to note that patients are going to be individualized and while the two mainstays of treatment are corticosteroids and tocilizumab, we need to be cognizant that there are other therapies that may not be FDA approved and may not have a lot of data at this point, but we should be familiar with. So I want to talk a little bit about anikinra. So anikinra is an IL-1 receptor antagonist that can be considered in specific cases. There have been several small case series reviewing the use of anikinra, both for the prevention and treatment of toxicities. All have employed various dosing strategies and schemas. In addition, responses have been very variable. To review the largest study that we have to date, it was a case series and they looked at patients that had both severe CRS and ICANs and were initiated on anikinra. Patients that were initiated on anikinra had a 73% improvement in their scores for both CRS and ICANs and a median duration of treatment of three days. Higher responses were seen in patients that received high dose anikinra, so right now it's very questionable about whether we should be escalating our doses of anikinra. And shorter duration of anikinra was associated with less improvement. In a study that was published out of our group, patients were given both, were given anikinra, so let's see, patients were given anikinra for high-grade ICANs in six patients and HLH for two patients. Half of the patients had clinical response and among the non-responders, patients were seen to have higher LDH, ferritin and CRP levels. So there's things that we can look at to predict whether patients are gonna respond to anikinra. There's several prospective clinical trials underway. We just closed a preventative trial at MD Anderson that showed significant benefit when starting anikinra early in a preventative manner, so trying to keep patients out of our ICUs and have lower side effects and could potentially result in the changing of the FDA label for anikinra. So to closing, I wanna say that CAR T-cell therapy continues to be a very promising therapy but associated with pretty significant toxicities that we as clinicians in the ICU can target and do something about and decrease length of stay for these patients and keep the mortality or the non-oncologic mortality low. Tocilizabab and corticosteroids continue to be our workhorse for these patients. Those select patients we're seeing increased use of anikinra earlier and were targeted so that we can reduce the incidence of both severe CRS and ICANs. Thank you for joining me and I will await the next speakers.

FDA-approved CAR T-cell products

toxicity profiles

cytokine release syndrome

neurotoxicity syndrome

IL-6 targeting with tocilizumab