Okay. So today, we're going to try and accomplish two objectives in the next 15 minutes, and that's to anticipate and recognize common adverse reactions or toxicities from select immunotherapies. And we're not going to talk much about immunotherapy in the context of COVID-19, since that was probably covered pretty thoroughly at other sections throughout the meeting. And next, we're going to identify strategies to improve education and communications across disciplines and specialties. I want to start by getting us all on the same page about what immunotherapy really is. And it's treatment that uses components of a person's immune system to fight disease. So I'm hoping that having this definition makes the concept of immunotherapy seem a little less nebulous. And I've included some examples to help illustrate the fact that immunotherapy can be used to treat a variety of types of diseases and in a variety of critical care settings. While chimeric antigen receptor T cell therapy, or CAR-T, and immune checkpoint inhibitors are two of the hottest topics in immunotherapy, there are many other contexts in which you might encounter immunotherapies. And so I hope this makes it feel a little bit more relevant to your practice, even if you're not interfacing with patients that battle cancer on a regular basis. So I think two good examples of that are monoclonal antibodies and IVIG. Here again are just a few more examples of specific products considered immunotherapy that you may have encountered in various settings. And so I think it's important to start here. As I was preparing this presentation, I reached out to a variety of multidisciplinary providers at other sites to try and get a concept of what questions and what hurdles they're facing in their own practices so that I could really have a good sense of understanding about this, not just at my practice site, but really on a broader context. And so these were some of the most universally asked questions after talking with specialists in infectious diseases, hematology, and critical care. And they may seem a little bit basic, but I think they're very important. And so over the next 15 minutes, my goal is to provide you some foundational knowledge that will help you tackle these and share some practical aspects for doing so. I think that awareness, education, and communication are really the core concepts of providing safe and effective care for patients who are receiving immunotherapies. And so today, I'm going to focus on awareness about specific toxicities or side effects that we can anticipate, as well as share some tools and tactics that can elevate our cross-disciplinary communication. I will give you some references to various resources for more in-depth education since we won't really have time to dig into many of these concepts today. We'll start with talking about monoclonal antibodies, because these are probably some of the most commonly encountered immunotherapies used in the ICU setting. You may see patients who are beginning therapy with monoclonal antibodies in your ICU, or they may require ICU-level care because of infusion reactions, which are probably the most common side effects class-wide. So these are characterized by fever and chills, shortness of breath and hypotension, and then occasionally some more obscure symptoms. And premedicating 30 minutes prior to the infusion can help reduce the frequency of these reactions, but it's not necessary with all of the monoclonal antibodies. So I've included a table here to refresh your memory on the nomenclature of monoclonal antibodies, and I want to call your attention to those that are murine or chimeric in nature. These are the ones with the higher rates of infusion or allergic-type reactions, because they're non-human products. So that means that commonly used monoclonal antibodies, like rituximab or infliximab, require premedications, but tocilizumab, on the other hand, does not. So the most common ones prescribed are acetaminophen and diphenhydramine, and steroids like methylprednisolone can be used in some instances. These are just some of the most commonly encountered side effects and the very basic steps of care. So again, infusion reactions are probably going to be seen most often, and those usually prompt an interruption of the infusion while the patient receives supportive care with things like steroids or further antihistamines. And then we typically resume these at a slower rate than what they were running at previously. On the other hand, if you see evidence of an IgE-mediated hypersensitivity reaction, that means permanent discontinuation of the agent, and therapies should be reevaluated with a disease specialist, and the patient would receive traditional supportive care like epinephrine, et cetera. A lot of people ask about the infectious complications of monoclonal antibodies, which unfortunately aren't very well characterized as a class. We know that agents that target tumor necrosis factor can increase the risk for granulomatous infections, and theoretically, all of these can increase the risk for bacterial and viral infections as well. These tend to be long-term complications, so they can occur weeks or months into therapy, and even after a patient has completed therapy with a monoclonal antibody. And so I think if you are receiving a patient that is being worked up or treated for infectious syndromes, having a heightened awareness of the possibility that this may be a viral infection or this may be a fungal infection is important. And if you have a patient who is contemplating the start of immunotherapy with a monoclonal antibody while they're in the ICU with you, it is important to look at product-specific recommendations for screening for things like tuberculosis or hepatitis. If possible, these patients may benefit from vaccinations before starting therapy, and sometimes prophylaxis against things like pneumocystis is indicated. We'll move into talking about CAR T therapies next. So in CAR T, a patient's own T cells are harvested and bioengineered to express a T cell receptor that recognizes and binds to a specific tumor antigen with very high affinity. They also express a co-stimulatory molecule, like CD28, that interacts with molecules on the tumor cell to prompt T cell activation and proliferation. There are six FDA-approved products available now that treat a variety of types of cancers. And broadly, the two most common toxicities that are unique to this therapy are cytokine release syndrome, or CRS, and immune effector cell-associated neurotoxicity syndrome, or ICANS. Infusion and sepsis is also very common for patients that receive these therapies, but that won't be within the scope of our talk today. So we'll start with CRS, which typically occurs within one to two weeks of the infusion, more often about one to three days. And this is an exaggerated inflammatory response that is a result of excessive cytokine release during T cell activation and proliferation. The hallmark symptom is fever, and it's also accompanied by things like tachypnea and hypotension. And ultimately, the consequences can lead to multi-organ system dysfunction. Then a management is largely product-specific and based on the grade of severity and organ toxicity. But I'll say that tocilizumab, which is a monoclonal antibody directed at interleukin is the foundation of supportive care in this context with or without steroids in some instances. This table demonstrates the grading of CRS, and I'll highlight that patients that have grade three or four toxicity or ones that progress very quickly through grades one and two are the ones you're most likely to see in the intensive care unit. And I'll draw your attention to the resources that are found at ASTCT, either online or downloadable app that's available on your phone, which can help with grading at the bedside. Those are very useful. And I also want to mention that a colleague of mine, Dr. Anne-Marie Brown, presented on these toxicities earlier in the meeting. It was on Saturday. And so she has an excellent presentation to refer back to if you want to learn more in-depth. And really that whole section talked about the advances in cellular therapy. So that's a great source of education if you're looking to learn more. Moving on to ICANs. This is a unique toxicity that can occur early in a patient's course, often concomitantly with CRS, but it can also have a delayed presentation. So all the way out to eight weeks after a patient has received their infusion. And here, symptoms can start mild with things like tremor or dysgraphia, which is poor and illegible handwriting. Patients may also have difficulty with word finding, so things like naming objects. That may progress to expressive aphasia or a total inability to speak. Patients can be lethargic. They can be inattentive. They may have apraxia, meaning you can give them a command. And while they understand what you're asking them to do, they cannot use their motor skills to perform the command. And then encephalopathy is a hallmark here. And the severe cases include elevated intracranial pressure, cerebral edema, seizures. And those, unfortunately, are often fatal. So here again, the management is often product-specific, often based on grade of severity. And tocilizumab can be used if CRS is occurring at the same time. But steroids, typically dexamethasone, are the foundation of supportive care. We're also seeing anakinra being used more often and earlier. And then many sites do use a cesareoprophylaxis once symptoms start to occur, even mild ones. These next two slides go through grading of ICANs, and I won't spend a lot of time on them. But they are here for you to refer back to. And this paper is taken, or this table is taken from a paper published by the CAR-ICU Initiative, which is a multidisciplinary collaboration of cancer centers, mainly across the U.S. And what this shows us is that despite a pretty high frequency of grades three and four toxicity that patients in the ICU experience, they do quite well. They had fairly low ICU mortality and low mortality specific to CRS and ICAN. So I think this is encouraging data with respect to the way we're able to get patients through the toxicities. Next up, we have immune checkpoint inhibitors. So these prevent the down-regulation of immunity by blocking co-inhibitory molecules, meaning that more of a patient's own T cells are able to be activated to fight their cancer. So immune-related adverse events are then inflammatory side effects that result from immune system overactivation. This is interesting that they can present within days of receiving a dose of immunotherapy all the way out to 12 months after an immunotherapy dose is given. And you can see by the picture here that almost any organ system can be affected. But the ones you're most likely to encounter in the ICU are probably going to be pneumonitis, hepatitis, myocarditis, and potentially some of the CNS toxicities like encephalitis, myopathies, Guillain-Barre, and neuropathies. These are graded on a scale of one to five, and therapy, again, is going to correspond to their grade. So I have a link here to a site that will take you through the organ-specific toxicity grading. So that can be very helpful if you'd like to refer back to that. And to just talk in generalities about treatment, steroids are most often going to be the go-to here. So the doses can range anywhere from a half a milligram per kilogram for grade two toxicities, up to one to two mgs per kg for grades three and four toxicities, and a gram of methylprednisolone for the more severe toxicity. There are other therapies that are used here. So we see infliximab used for colitis. You would see hormone replacement therapies for endocrine toxicities. IVIG and plasmapheresis are used for CNS toxicities. And there are other agents like mycophenolate and others that are used as either second line or salvage treatment when patients aren't initially responsive. And so the two citations at the bottom of this slide are good guidelines to refer back to with respect to treatment of specific toxicities at specific, and specific grades. Generally once patients arrive in the ICU, their toxicity is severe enough that further doses are held, and the decision to re-challenge is really made with the disease specialist. In these last few slides, I want to highlight some of the intangible things that we can do to promote safe and effective treatment of patients who receive immunotherapy in the ICU. And we're going to start with communication, which unsurprisingly was one of the areas of opportunity that was commonly cited by those people that I reached out to. If you recall back to those common questions, one of them was, who do I talk to about whether or not this is toxicity or how we treat it? And so identifying a co-primary or an inpatient consult team with the right specialty and expertise and engaging them early is key. Inpatient teams, as opposed to outpatient specialists, are often available more readily, and they can be at the bedside in person with you, which is very helpful. And so some specific tips that I wanted to recommend are to keep their contact information handy. Make sure people on your team know where to find it. Proactively identify a person overnight or a pager overnight that you can call with questions. The other thing you can do is try and leverage their familiarity with specific things to make sure that we're doing the right things in the ICU. So one example is that the APPs on our HEMONC teams will come and help us perform ICANN's assessments at the bedside on a regular basis. It's also very important to take a comprehensive history, and I know this sounds like fundamental. Of course, we always do this, but this is especially important when you're receiving a patient that is being treated for cancer or that has been treated elsewhere at other institutions and is coming to you as a referral, because you really need to know what they have received elsewhere so that you can inform your differential diagnosis correctly. And gratefully, this is getting a little easier with things like shared EHR platforms like Care Everywhere with an Epic. There are other tools that I've seen used. For example, I've seen best practice advisories or alerts in an EHR indicating a patient has received immunotherapy at any point in time in the last 12 months. You can also access their prior chemotherapy plans occasionally using programs like Beacon with an Epic. So if you do a little extra digging, you can actually go in and see what the patient has been receiving. And in the absence of being able to use these tools, you can always ask the patient. Ask their family. Don't be afraid to ask for the primary disease specialist contact information if you're really struggling with your differential diagnosis and you want to gather that additional information. Systems-based solutions are also incredibly powerful tools to make it feel like you don't have to reinvent the wheel every time you treat a patient with immunotherapy. So I highly encourage you to develop things like formal order sets, protocols, workflows, and clinical decision support. And these need to be developed with multidisciplinary, multispecialty engagement, and then routinely re-evaluated to make sure that they still reflect the current state of clinical practice as well as health system structure. It's also, let's see, oh, when you are dealing with a rotating pool of trainees or a really big core group of consultants or providers that come to the unit, it can be helpful to identify those people that are a consistent presence. Target them for higher level education so that they can be an ambassador when those rotating staff come through and they can point them to the right direction and resources. I've included a couple examples here of the types of tools that I'm talking about. So this is a clinical decision support example for recommendations for a patient who has probable immune checkpoint inhibitor pneumonitis. And here is an example of an order set for a patient receiving rituximab. So it helps the prescriber to navigate the biosimilars. It has pre-checked, pre-medications that are appropriate as well as rescue medications. So these are just a few examples. And I'll close by emphasizing the importance of good handoff when patients transition between levels of care. We needed to be assigning tasks to the right team member or the right team and documenting those things in the EHR for clarity. It can also be really helpful to try and forecast what patients might need. A great example of this is identifying the need for stress ulcer prophylaxis or pneumocystis prophylaxis for a patient who's going to receive a prolonged course of steroids for immune checkpoint inhibitor toxicity. If we take the initiative to start those therapies while we're in the ICU, we risk potentially unsafe gaps in care at transitions. So I will close with that, and thank you very much for sticking it out with me.

immunotherapy

monoclonal antibodies

CAR-T cell therapy

adverse reactions

communication