What is cytokine release syndrome? Why does it happen? So cytokine release syndrome is a fancy terminology that really describes the immune system's reaction to being challenged with a specific antigen. It's the same kind of reaction that many patients will have to an infection as they become developing sepsis or septic shock, for example. So cytokine release syndrome, or CRS, is being used as a term for patients receiving CAR T cells or by specific antibodies where the T cells are being activated against a certain antigen. They're releasing a lot of chemicals that increase the body's ability to weed out these cancer cells just like you would for an infection. But as a result of that, the blood pressure may go down, patients can develop fevers, you know, all of these kind of symptoms take you down the path of this cytokine release syndrome that needs to be managed and controlled with supportive care measures as well as treatments such as tocilizumab or steroids. So you know, of the many side effects of CAR T therapy, the most common side effect that we think about and talk about is CRS, or cytokine release syndrome. Cytokine release syndrome is basically a hyperinflammatory state. Your body is revved up because these T cells have seen all these myeloma cells recognizing all at once and you have fevers, feels like you have the flu. You don't have the flu, you don't have an infection per se, although people certainly can have infections on top of CRS, but CRS at its core is a hyperinflammatory state, loss of inflammation. What that practically means in terms of symptoms and signs to look out for, fevers are by far the most common manifestation of CRS. In this setting, because so many patients after CAR T therapy have lower immune system, we use the cutoff of 100.4 degrees Fahrenheit or higher, 38 degrees Celsius or higher as a cutoff for a fever. With very low body temperatures, if it's 96 degrees or 97 degrees Fahrenheit can also be a sign of CRS. CRS can also manifest as low blood pressures, fast heart rates, difficulty breathing and so forth. Those symptoms often come in the presence of fever. In terms of what patients and caregivers need to look out for, the most important thing I would say that your homework when you undergo CAR T therapy is to make sure that you have your doctors and CAR T coordinators and nurses' numbers on speed dial because they're the ones who can rapidly triage what's going on and figure out what to do about it, whether you're at home or in clinic or so forth. Certainly a fever is a reason to call immediately. If you feel feverish, check your temperature. I tell my patients I should check their temperature one to two times a day, even if they feel well, just because sometimes when CRS happens, it can happen very quickly depending on the CAR T product. More serious cases of CRS can involve low blood pressure, which can manifest as dizziness or lightheadedness or fainting or difficulty breathing, shortness of breath that can sometimes in very serious cases require a breathing tube. We grade CRS on a scale from zero to four, really. All toxicities that all of you will see are graded from zero to five. Five is death, so obviously very much avoiding that. Zero to four for CRS, zero is no symptoms. One is just a fever. Two is when the fever happens, but there's also something else going on like low blood pressure, difficulty breathing. Three is when you're acquiring almost an ICU level because you're meeting an intensive care unit level of medications to support your blood pressure, medications to support your breathing. And four is life-threatening. As we've gotten more experience with CAR T therapy, I will say even in the last five years, we've gotten much better at preventing early-grade CRS, meaning just a fever, just grade one CRS from progressing to life-threatening CRS, meaning grade three or four, it still certainly can occur. What's changed in the last five years is that we've gotten much better at recognizing and encouraging our patients and caregivers to detect CRS very early when it happens. And when it happens, we can give medications to just tamper, just tone down, put a little bit of the brakes on the immune system, not shut down the immune system, not give very high doses of steroids that will kill the CAR T cells, but low doses of steroids or low doses of anti-inflammatory medications, one of them being tocilizumab or Actemra, that can help prevent early-grade CRS, just a fever from becoming late-grade CRS. We used to be concerned, if you had asked me five years ago about whether it's good to get CRS, I think at the time we used to think that, well, maybe a little bit of CRS is good because it shows that something's happening inside of you. And I think increasingly we're knowing that it's just impossible to say. So what I tell my patients when they're being hospitalized for CAR T therapy is that the two-week hospitalization is purely to see if CRS happens and manage it if it does. It's not to tell if the CAR T cells are working or not. If someone gets CRS, great, we'll take care of it. If someone doesn't get CRS, totally fine. We'll find out in a month or two how well the CAR T cells work and furthermore, but there's no clear correlation between CRS and the efficacy of these CAR T cells. Do you know if any remote monitoring of CRS is being investigated and what does that mean? So an excellent question in the research area of mine is how can we move CAR T therapy from the hospital into clinic and how can we move CAR T therapy from clinic into the home as much as we possibly can. And so the big three side effects of CAR T therapy, again, CRS, eye cancer, or toxicity, and immunocompromised, the CRS is unique in that the best way to detect it is fevers, monitoring, detecting a fever when it happens. And so I tell my patients when they're at home to check their temperature once or twice a day. I think an exciting avenue of innovation in this space and one that I'm really actively researching is the idea of remote patient monitoring. So devices that ideally can check your temperature for you every 15 minutes just by a patch on the skin or the chest that don't require any extra effort from the patient. I think two, we're not there yet. I think two challenges need to be overcome for those to become the standard of care that we routinely do for our patients. One we have to prove that they're actually tolerable for patients. I don't use the word toxic or not because I don't think it's ever life threatening to have a device put on your skin. But a lot of them are actually not that user friendly just yet. And that's one of the areas I'm working on with our partners to figure out how to just make them more easy for patients and caregivers to use, less bulky, less likely to cause sweat. Some of them I've seen that are almost like a giant pager that patients have to carry. That's a lot to ask a patient to carry a 10 pound weight around with them. And so every year we're getting better at that and transmitting the data in a user friendly manner. And so the second component, that's kind of just the tolerability of it. And the second component we have to figure out is the action ability of it. If that temperature probe detects a fever, a near fever, what do we do with that information? You know, in real life what I would do is if someone told me that I would say, go check your temperature the old school way with a thermometer and tell me what it is and let's act accordingly. But we don't know. I think a big debate in the field of remote patient monitoring is should the patient be getting all the data points in real time? Should the doctor be getting all the data points in real time? Or should it be going to a third party, what I call a care traffic control center, like a digital warehouse that kind of figures out what signals need to be sent to the patient or sent to the doctor because no patient wants to have their phone beeping every 15 minutes saying your temperature was 98.6. No doctor wants to deal with that because we're taking care of patients. I don't want to see normal temperatures. If someone, if I know they have a fever and I've already given them therapies to get rid of that fever, I don't want it over 15 minutes, nor does a patient in the middle of the night that they still have the fever. So there needs to be a way to make it that it's actually improving how we deliver care, not just becoming another useless data point. And so that's something that I think I'm really working with these companies to try to do in a better way. And that's one of the areas where patient advocacy is imperative because here the correct answer is what the patient says in terms of the tolerability of this device and how much data they personally want or do not want. And I want there to be some customizability because some patients, to be honest, don't want to know. Like they really do not want to see their temperature every 15 minutes. Some patients really want to know the patients that have fitbits and so forth. And so along with that customizability, I think will be really important for this. When does CRS usually occur? The $1,000,000 question for cytokine release syndrome or CRS is when will it occur and how quickly will it occur? So both the kinetics wise, when will you first notice that fever? And then from the time of the fever, how quickly does it get serious if it is going to get serious? And it's tricky because that can depend on a lot of factors across different types of CAR T therapy, including ones that are on clinical trial. Actually our group has researched this and found that, for example, disease burden may Patients who have a lot of myeloma cells inside their body that are detectable by bone marrow biopsy or by lots of plasma cytomas, they may have more CRS, a more quick CRS. We're increasingly realizing though that it also depends on the product. So in general, I'd have Capsa gene, Biclusel, IDSL, Abecma. The kinetics of CRS tend to be faster there. More patients there get CRS within the first day of their infusion. Usually I would say within the first week in the vast majority of patients. But on the flip side, it's kind of fast on, fast off. Most of the patients, the fevers are gone shortly thereafter. With Ciltacapta-genital-lucil or Ciltacell or Carvicti, it tends to be slower kinetics because of how the CAR T cell therapy is designed. The CAR T cells take longer to turn on, longer to get angry, longer to creep the cytokines that produce cytokine release syndrome. So on average, typically around five to seven days afterwards, depending on the trial is when CRS first manifests. At the end of the day, the percent of patients who get CRS have that fever of some sort. It's about similar between the two cohorts depending on the trial. But again, as you alluded to across studies, patients who get Carvicti or Ciltacell tends to manifest later. The reason I said it's a million dollar question is if someone's going to get a fever on the day that they get the CAR T cells, it probably does make sense to keep them in the hospital because it's supremely annoying to have to be at home and then be asked to go back to the clinic, back to the hospital after you were just there because you have a fever. And so they probably are going to be hospitalized for CAR T therapy. If we can get to a point where patients can stay at home for three or four days, not have any side effects, and if they get a fever it's only after a couple of days, we could probably do the CAR T therapy as an outpatient, have the patient be at home, which is a win-win I think for patients and for hospitals and for health care systems. And I think it's a really attractive possibility. I do want to emphasize that that's not absolute. I've personally had patients who have had a fever on day two after CAR-VIC-D, but again, every patient is unique. But I think figuring out who's going to get CRS early and acting accordingly is, again, a setting area of research. And perhaps maybe it will be the wearable probes that will tell us how to do that. Maybe with a wearable patch we will tell that the day before the fever, the patient's temperature doesn't hit 100.4, it doesn't hit 38 degrees Celsius, but it's kind of whipping like this more than before. Let's do something about it. And I think we don't know that that's the correct approach yet, but hopefully five years from now, ten years from now, we'll get there.