What is Immune Affector Cell Associated Neurotoxicity Syndrome, or ICANs? So ICANs is a fancy acronym which essentially highlights the neurotoxicity that patients can have when they're receiving CAR T cell therapy or bi-specifix. So if you're going to simplify things, neurotoxicity typically tends to happen independent of CRS, but the mechanisms are somewhat similar because there is leakiness to the blood vessels as a result of the immune system being activated. The brain can be affected as a result of those cytokines and then leakiness of the fluids. And this is where steroids can help in mitigating that kind of side effect. Usually neurotoxicity tends to happen earlier, within a week or so of receiving a CAR T cell therapy or bi-specific antibody. But in some cases, you can see some delayed effects too. We're very excited at the really high response rates we're seeing with CAR T therapies, especially in very highly pretreated patients. But it does come with a cost, which we're still learning, although we have come quite a long way. Sometimes the T cells can say, become overly excited when it's a systemic issue, we call that CRS. In a few patients, that over excitement of the T cells happens in the central nervous system and we call that ICANs. So the neurotoxicity does vary with the different products. I think it's one of the, it's a concept that is universal to T cells, but the timing and the severity and the specific symptoms seem to vary between different products. With the currently approved products, we have a Beckma, which has a fairly low incidence of ICANs. We do monitor patients throughout their stay with us. And usually again, with that product specifically, these are early events which are captured in the two weeks we tend to keep patients in the hospital for close monitoring. Our newer approved product is called CARVICTI and that has a different profile, not only in timing, but also in how it manifests. So in addition to the confusion, aphasia, which is a difficulty forming words, a difficulty writing, all of these things again, in these tests that we do, asking patients to write a sentence, draw, answer a few questions, count backwards. We're able to pick them up any symptom or any change early on. The interesting thing with the CARVICTI is that in addition to what we call ICANs, there are some other neurotoxicities that can be delayed. And this highlights the importance of not only the close monitoring while you're in the hospital for those first two weeks, but having a caregiver who is really by your side for a minimum of two months at this point. Again, that will capture most cases, but it's something to keep in mind just to be aware that seizures and Parkinsonian symptoms have happened sometimes weeks to months after the therapy. Very rare, but they have been reported. What are some of the symptoms caregivers need to look out for while monitoring people taking CAR-T? As a caregiver, you are in the best place to judge any changes in character, personality, speech. So if you are caring for a patient who's recently been through T cells and they suddenly are not speaking themselves, are moving more slowly, don't seem to understand questions, just really tends to be fairly subtle things that are not themselves are picked up very quickly by caregivers. Are there different rating systems of ICANs? What are the most common that we are seeing? Similar to CRS, we do have grading patterns that have been standardized and depending on the presentation and severity, that dictates the management strategy. We use an ice scoring test. This is what I had alluded to earlier that we test patients usually every eight hours to make sure that they can count backwards. They know where they are. They're able to draw a certain shape. They're able to write a sentence and based on these 10-point testing, we evaluate their need for an intervention. So a zero to two, you know, they're subtle. We may not need to intervene. We may check them much more closely. As they get a score of 10 means you got all your points correct. As you miss the questions on the ice testing and that number is lower is our concern for need for intervention. The specific intervention may depend on whether it's happening at the same time as CRS. So CRS, we tend to start with tocilizumab as the antidote. For ICANs, we tend to use dexamethasone. And there's a lot of work trying to understand the timing and dosing of the steroids because these are all therapies that target T cells. And we've just worked very hard to engineer these T cells. In the early days, I think one of the concerns and why we had so much more toxicity is we were very hesitant to treat patients or, you know, risk getting rid of these very precious T cells. We've learned over time that the use of TOSI or even steroids still allows for the deep response rates and just abrogates the toxicity. One of the concerns with the use of steroids is that we are seeing an increase incidence of infections. And so suppressing the immune system may come at a risk of higher infections. So trying to get the ICANs treated quickly and slowly taper off the high dose steroids is currently the best that we can do for our patients. What is ICE Scoring? So ICANs is one of the toxicities we concern ourselves when the T cells, I would say, misbehave, get overly excited and affect the central nervous system. So we use a monitoring tool called an ICE Score where there are 10 questions that we pose to patients at regular intervals and measure any changes from baseline. And those include things such as writing a sentence, drawing, counting backwards, location and then things like that. A 10 out of 10 is where we start and hope to stay. If you miss a few of the questions and the score is somewhere between 7 and 9, we would call that grade 1 and may not require further intervention. Usually more testing, more evaluation, but we try to defer intervention to grade 2. So once your score is between a 3 and a 6, that would be grade 2 and it's where we usually feel compelled to start dexamethasone or some kind of steroid therapy. Grade 3 are the 0 to 2 and again, these are patients who are harder to arouse, may actually need an escalation in care, say to an ICU level of care. And 0 is when we really can't get a response and those are very, very few. But the severe cases that we don't ever want to let escalate. What is the most common grade? Absolutely grade 1. So I think over time, in the early days, we were fairly hesitant to start steroids from concern of getting rid or damaging the CAR T product and thus losing our response. We've learned over time that use of steroids really seems to abrogate the toxicity without affecting the effectiveness of the therapy. And so using it quicker really has limited the incidence and you will see that with data as we move forward. Does ICANNs usually coincide with CRS? So different products will have different timing and it can happen at the same time as CRS or on its own. I think most commonly CRS is by far a more common toxicity and again, as we are learning our mitigation strategies, up to 80% of patients in certain studies will have had CRS, whereas newer products are really under 50%. So we're getting much better in other disease states like lymphoma. They actually have studies using prophylactic tosalluzumab to prevent it and not even allow patients to get that early. If they're high risk patients, trying to prevent it rather than allow it to happen. We haven't done that in myeloma yet, but I think in part it's because our incidence of toxicities are lower. So ICANNs, if it is happening in the same setting as CRS, we can add the steroids to TOSI, but if they are not having any CRS, which is again very uncommon for them to have isolated ICANNs, dexamethasone alone should be able to reverse it. And I think that's the other important thing to keep in mind is even though this is known toxicity, we are preemptively looking for it. And so our chance to nip it in the bud at first sign and really reverse it. Many times things like fevers, which is the cardinal sign for CRS, can be scary in our patients because we don't know the cause. In these cases where we are ready, we're expecting them to have it, we're expecting it in a specific window, we know exactly how to respond to it, the nurses on the floor know exactly how to respond to it. It's a very more predictable and less scary situation. CAR-Ts are predominantly known to develop cytokine release syndrome, which is essentially a syndrome that looks very much like the patient's septic. They have fevers, they have low blood pressure, and they feel sick. The other big side effect we worry about is some type of neurotoxicity. And this is when patients, on average, can develop over an array of things that affect their cognition. They can develop seizures, confusion, memory loss, and these can either be short-lived or they can be long-term. The majority of patients who have some type of neurotoxicity have also had CRS. So if you haven't had CRS, it's very unlikely for you to develop some of the neurotoxicities associated with either of the FDA-approved CAR-T products.