Here are my disclosures related mainly to pulmonary hypertension. So today I'll be reviewing toxicities of immune checkpoint inhibitors and other targeted therapies for cancer. Specifically looking at immune effector cell therapy, specifically cytokine release syndrome and ICANS, which is the neurotexicity associated with immune effector cells, toxicities related to monoclonal antibodies, and immune checkpoint inhibitors. So really when I think about the toxicities that occur with these remarkable therapies that have come out on the market in the last 20 years that have changed the way that we look at cancer therapy, I try to understand what is it trying to do. We've talked a lot at this conference, I feel like over the last few days, about immune dysregulation, particularly in relation to sepsis and immune paralysis. Well in immunotherapy we're doing exactly the opposite. What typically happens with your cells is that your T cells should recognize the non-self cells, i.e. cancer cells, and kill them. Well the cancer cells then develop immune editing and they evade our natural immune responses. So immune therapy is just revving up your immune system to then kill the cancer cells. And so when we look at that, it's the immune effector cell therapy, specifically CAR T, which has revolutionized our hematologic malignancies and improved outcomes, but is associated with some pretty severe and potentially fatal toxicities. Monoclonal antibodies, which also have a number of toxicities, and immune checkpoint inhibitors, which again has revolutionized some of our solid organ malignancies, specifically in lung cancer, sarcomas, melanoma, breast cancer. The toxicities are mainly related to this immune response, so the hyperinflammatory response that leads to end organ damage. We can also have antigen mediated that is an on-target, off-tumor effect. And that recognition of the tumor antigen causes some unwanted side effects that ultimately lead to organ failure, and this is when they present into our intensive care units. As I mentioned, it's exploded over the last 10 to 20 years, and we're going to continue to see an explosion of immunotherapy. There's over 200 CAR T trials out there right now looking at not just in hematologic malignancy, but solid organ tumors and even autoimmune disease. So at some point, you will always see a patient in your ICU that has a toxicity related to this or is undergoing treatment with it for an oncologic diagnosis. This is just really a few of the different therapies, and just to show that it continues to increase over time. Specifically looking at CAR T cells, as I mentioned, it's been a revolutionary therapy. It's very exciting because it has a durable and lasting response, and patients who were relapsed or refractory are now living longer, and so that's incredible. But what can happen is they can develop CRS and ICANs. So when you think about CAR T therapy, it can be autologous, which is the majority of the patients receive, or allogeneic. So with the autologous, the cells are extracted from the patient. They then undergo some viral, they use a viral vector to inject the antigen into the cell. The cells undergo expansion. The patient receives conditioning therapy, and then the cells are re-infused into the patient. It's considered a living drug because it has a durable and lasting response, which is important to note because some of the effects of CRS depend upon when that expansion occurs. So in some forms of CAR T, it can happen within the first one to two days, where you have more rapid expansion of the cells, leading to an increased inflammatory response and cell death, or it can be a slower expansion, and that may happen in the next four to six days after infusion of the cells. So there are six different CAR T products out on the market for relapse or refractory lymphomas, and more recently, multiple myeloma. As I mentioned, there is a number of toxicities, specifically we hear about CRS, which during COVID became a hot topic as well, but was familiar to many of us taking care of these CAR T patients prior. And then immune effector cell-associated neurotoxicity, or easier to say, ICANs, HLH, or macrophage activation syndrome, tumor lysis syndrome, delayed effects can be hypogammaglobulinemia or B-cell eplasia, and then infection. Infection is always key in these patients, and even bacterial and invasive fungal infections can occur. Today, we won't touch on that that much, but any of us that are intensivists will always have antibiotics on board in these patients. CRS is a clinical syndrome that's really a supraphysiologic response that is in reaction to the CAR T cells. The prevalence varies, and it depends on the CAR T construct, but majority of patients will have a form of CRS. Severity of CRS can occur in about 30% of patients, so it will land in the ICU. And about 20% of patients require high-dose vasopressors. It usually appears within the first seven days, but again, it can vary depending on the CAR T construct or the underlying malignancy, and can even occur at about 10 weeks' time. So this is looking at what happens at the cellular level, and it's mainly driven by a cytokine release. So the cytokines that we focus on are typically IL-6, and that corresponds to the peak of your CRS, IL-1, TNF-alpha, interferon gamma, and that determines the severity. We know that higher levels of interferon gamma and IL-6 correlate with SOFA scores and overall morbidity and mortality. Here's a schematic looking at the time frame from when you would see peak CRS and ICANs. CRS and ICANs can overlap, which is important to note because it's treated differently than if you have ICANs alone. When we have CRS concomitant with ICANs, we treat with tocilizumab targeting IL-6 and corticosteroids. When you have ICANs alone, you're typically treating with corticosteroids, and in many centers now, anakinra targeting IL-1, but not utilizing the IL-6 pathway that may actually increase the severity of the neurotoxicity. Here's the grading system. Patients will present into the intensive care unit at grade 3 and definitely at grade 4 as they start on vasopressors and have increased oxygen requirements. The CRS grading system is based upon fever, hypoxia, and hypotension. You cannot have CRS without fever, but it also depends on whether or not they received an antipyretic or if they had received a dose of tocilizumab that could blunt that febrile response, so taking the patient as a whole is always important. The management is really, there's not a great set of guidelines right now to guide you, but each institution has their own set of guidelines, and it's based upon corticosteroids and IL-6, as I mentioned. Anakinra is also being utilized, particularly in refractory cases. ICANS is also very common, occurring in majority of patients, and severity can be in 30 to 40% of patients. It can be fatal, particularly if it presents with cerebral edema and status epilepticus. The duration, it can be 10 to 15 days, which is hard when you're watching a patient who's incredibly encephalopathic, but most of these are reversible, particularly if it happens in the acute phase and occurs with concurrent CRS. The symptoms can range from minor things such as dysgraphia, tremors, inattention, all the way to status epilepticus and seizures, or excuse me, and cerebral edema. Here's the grading system. Again, grade three to four should land a patient in the ICU, so we should be familiar with how we will treat them. We would for anyone with seizure disorder or increased intracranial pressure, it's nothing different besides our standard of care. Monoclonal antibodies have also a number of side effects. The hypersensitivity reactions or infusion reactions typically occur acutely. When you think about it, it can be an IgE-mediated or non-IgE-mediated anaphylactic or anaphylactoid reaction. Most of them will occur at the second infusion, except for cetuximab, which can occur with the first infusion. CRS can also occur with monoclonal antibodies and can be difficult to differentiate between an anaphylaxis reaction. So typically, if it's hours after the infusion, you think it's more CRS than it is an infusion-related reaction, but again, it's hard to always differentiate. Cardiac toxicity can occur, pulmonary toxicity with pneumonitis, thromboembolic events, neurotoxicity with press, ischemic stroke, intracranial hemorrhage, aseptic meningitis, encephalopathy, and then renal toxicity with interstitial nephritis, thrombotic microangiopathy, tumor lysis syndrome. Here are some specific monoclonal antibodies that have higher incidence of different types of toxicities, and so being aware of which drug the patient was on and what toxicity can occur is also important. Immune checkpoint inhibitors typically seen in our solid organ malignancies, PD-1 and PD-L1 and CTLA-4, they're really taking the brakes off of the immune system and trying to rub it back up to, again, kill those cancer cells. So when we see toxicities, it's the immune-related adverse events. Pneumonitis can occur and is treated with steroids. Determining the grade is really important for any of these toxicities because as oncologists look to re-dose the patient, it depends on the grading system. The NCCCN guidelines have specific grading systems and recommendations for treatment. We can detect toxicities with myocarditis, pericarditis, and dysrhythmias. The myocarditis is incredibly rare but is very fatal, and so being aware of the fact that myocarditis can occur is important. Myocarditis also can occur with myasthenia gravis and myositis, and so looking at different features of that just to keep on your radar. Neurotexicity, as I mentioned, myasthenia gravis is one. Myasthenia gravis does not present like our typical bulbar or ocular manifestations initially. It's more of a respiratory event, so that's where we'll see these patients, coming into the ICU. And you're treating with steroids, which is different than we would for any other form of myasthenia, Guillain-Barre, cerebral edema, aseptic meningitis, and PRESS, and seizures. Neurotexicity, again, tumor lysis syndrome, interstitial nephritis. Neurotexicity can occur, and infusion reactions can occur but are rare. The pathophysiology on why we're having a response is predicted based upon loss of self-tolerance. Do they have underlying subclinical inflammation? Do they have an underlying autoimmune disease? And there can be molecular mimicry as well. We're learning more and more about the microbiome. I think there's another session going on talking about microbiome right now, but we've found that, particularly in the gastroenteritis and immune-related adverse events related to GI, it can reflect the underlying microbiome and determine the severity of their toxicity. So I think it's incredibly fascinating, a lot more to learn. There are 70 different toxicities that can be associated with immune checkpoint inhibitors, so it affects every organ system. And so anything that a patient comes in with, it should be on our radar, so we will see all of it. The severity can be severe in grades 3 to 5, and about 20% to 60% of patients, depending on the underlying malignancy and the drug, can happen in the ICU. It's not as predictable as the time course that we'd see with chemotherapy or radiation therapy, and it varies between agents. I really like this schematic here that looks at the amount of toxicity, but then the severity of it. So with PD-1 and PD-L1, it's very common to have a colitis, but typically does not result in severe disease where they have perforation or land in the ICU due to their enteritis. However, you can see that with myocarditis, very rare, but it's all red because of the high mortality. Pneumonitis also has significant morbidity and mortality associated with it. Here is some form of a time course, but again, it can vary. Most do occur within the first three months, but can actually even happen after discontinuation of the drug. Risk factors are patient-specific, so if they have underlying autoimmune disease, ILD, tumor-specific, a high disease burden, specific types like melanoma have more associated colitis, agent-specific. The recognition is key to management. We think that about 16% of ICU admissions were drug-related, and that's really an underestimate of what we're seeing, and again, it's going to continue to grow. So really working with your oncologist in a multidisciplinary fashion is incredibly important for us, how to manage these patients, because it also has long-term effects. We don't want to limit someone's therapy that could be potentially lifesaving if we're able to get them through that event. The prognosis depends upon the underlying toxicity, and again, myocarditis and pneumonitis have a higher prognosis, or worse prognosis. Here is a very busy slide, but it's just kind of a nice approach to how to manage immunotherapy-related toxicities. You think about when did they have their product. Was it CAR-T, a monoclonal antibody, an immune checkpoint inhibitor? Which one was it? How many days from onset? What type of organ toxicity? And then breaking it down from there. When I think about patients that come into the ICU with cancer, I think, do they have a disease that's just unrelated to cancer, or is it related to their antineoplastic therapy? Is it tumor progression, or is it a malignancy-related complication? And so these are the ways that I try to approach patients that come into the unit. Thank you very much. Appreciate your time. Thank you.

immune checkpoint inhibitors

CAR T-cell therapy

cytokine release syndrome

immune effector cell-associated neurotoxicity

monoclonal antibodies