BETA - What is delayed neurotoxicity?

CAR T-THERAPY CAR T-THERAPY has opened new doors for many people living with cancer. But like all powerful treatments, it can come with side effects, some of which may appear later rather than right away. One of these is delayed neurotoxicity, which affects the nervous system. In this video, we'll explain what delayed neurotoxicity is, what symptoms to look for, when it can happen, and how it's monitored and managed so you can feel informed, prepared, and supported. What is delayed neurotoxicity? How does it differ from immune effect or cell-associated neurotoxicity syndrome? Some CAR T-cell toxicities are seen with almost all CAR T-cells, and then some CAR T-cell toxicities are only seen with certain CAR T-cells. So ICANs is a type of neurologic toxicity of CAR T-cells that seems to be seen with almost any CAR T-cell product. ICANs is an acronym. It stands for immune effector cell-associated neurotoxicity syndrome. You can think of it as neurotoxicity from CAR T-cells. It's thought to develop as the CAR T-cells are growing in the body, they release and trigger certain chemicals that can mess up the brain a little bit. In most cases, ICANs is a short-lived thing that might require some steroids, but there are rare cases where ICANs can be severe and even potentially fatal. But ICANs usually happens early. It happens right around the time that you get cytokine release syndrome, usually in the first couple weeks after CAR T-cell therapy. There's a separate set of neurologic toxicities that are late neurologic complications. These later neurologic complications seem to be specifically seen with BCMA CAR T-cells for myeloma. They're not usually seen after lymphoma CAR T-cell therapy. They seem to be specific to the CAR T-cells that target BCMA, and those are only myeloma CAR T-cells. Silt-a-cell, as the product that is more potent, seems to have a higher risk of these delayed neurologic toxicities. They can happen early sometimes within the first few weeks, but more often they're a couple months out. Within the first few months is when most of them develop, but not as early as ICANs. What types of delayed neurotoxicity have been observed following BCMA-directed CAR T-therapy? There's a variety of these delayed neurologic toxicities that can develop. One of the more common ones is called a cranial nerve palsy. Some people are familiar with the term Bell's palsy. Bell's palsy is a syndrome that anybody can get where the nerve that works their face gets sleepy. Patients can develop a weakness in the face, and it can be scary because it looks like sometimes somebody's having a stroke. That can happen to any of us. It does seem like patients after CAR T-cell therapy can develop a facial nerve weakness that looks just like Bell's palsy, and that's one of the delayed neurologic toxicities. We can also see other nerves of the head and neck affected. Some patients have developed a loss of the sense of smell, which could be from the olfactory nerve being affected, which is one of the nerves of the head and neck. Other cranial nerves, like the nerves that work the eye and control eye movement, can be affected. You can see any of these, what we call cranial nerves, affected. These are usually temporary things that get better over the course of days to weeks, but there are some patients who have not had recovery from some of these cranial nerve palsies. Another category is peripheral neuropathy. We've seen patients develop problems with nerves that work the rest of the body. One of the more common ones that we've seen in our practice is one of the nerves that works the arm and shoulder can get weak. I have one patient who had a lot of difficulty raising his arm and doing certain things that required him to put his arm above his head. We've seen that occasionally. It also tends to be temporary, but not in all cases. Some patients have some long-term residual dysfunction. The most concerning one that we've seen is this delayed neurologic toxicity that looks like Parkinson's disease. Parkinson's disease, of course, is the disease where you lose a little bit of control over your movement. Patients have trouble initiating movement, initiating speech, and so they often have an appearance of being just very, very still. They don't have the normal kind of movement that all of us have as we try to sit still, but we're always moving a little bit. Patients with Parkinson's disease have difficulty making those movements, and patients with this delayed neurologic toxicity that looks like Parkinson's disease have a similar type of problem. That also manifests in difficulty writing and difficulty with fine motor tasks, and it also manifests as cognitive problems. There is a cognitive component to this delayed neurologic toxicity also. We have seen patients develop this and get better, but we've also seen patients develop this and either it be irreversible or even potentially fatal. Are there any risk factors or biomarkers that can help identify patients at higher risk for developing delayed neurotoxicity after CAR T therapy? We think patients are at higher risk for these if they have a lot of robust growth of CAR T cells after the infusion, and especially if they have a lot of CD4 CAR T cells compared to CD8 CAR T cells. So we're starting to look at that earlier on, and we're testing some interventions to calm down those T cells before they develop these late toxicities in patients who are at risk for them. Can the amount of myeloma in the body going into CAR T therapy affect the likelihood of delayed neurotoxicity? When you looked at the original CILTA cell trial, the CAR TUT1 study it's called, where they had about 100 patients and a handful of them got this delayed neurologic toxicity, it did seem like the patients with higher disease burden had a higher risk of that. And that's one of the reasons more and more we are trying to get patients' disease under good control as we give them the CAR T cells. So patients are going into CAR T cell therapy with less myeloma burden. And the idea is that maybe that the T cells are not so excited when they go into the patient's body, because the T cells, if they go into an environment where there's a lot of myeloma, they get hyper stimulated, they grow very quickly. And that could put those patients at higher risk of developing some of these complications that come from over activation of CAR T cells. And so we do think that that is a potential risk factor. With CAR T cells approved for earlier line of therapy, it's now a little bit easier to get patients' myeloma under good control before they get CAR T cell therapy. So when they, CAR T cells were first approved, they were only, you could only use them in patients who have exhausted most of the standard therapies. And the result, the patients coming into CAR T cell therapy had a lot of myeloma. Now that we can use CAR T cells a little bit earlier, we don't have to wait for the disease to become so resistant to therapy. And we have better options to get the disease under good control before we give CAR T cell therapy. So this is something that has been looked at on the clinical trial setting, not necessarily in the real world setting. And I can give you a bit more information on that. So on the clinical trial, there are several features. So for example, having very high disease burden or what we call tumor burden. So this is reflected as having a high monoclonal protein or M spike, like let's say B on five, or having somebody with really high light chains or a lot of disease in their bone marrow. These are patients that are at increased risk for developing this neurologic toxicity. We are currently working with Janssen on the commercial side to develop almost like a predictive model to look at certain features, not only clinical characteristics from the chart, but some biological markers. So some blood testing, bone marrow testing, sometimes spinal fluid testing or PET scans to see what are some predictors that can identify who these high risk patients are and what we can do to improve their outcomes. But generally, one of the most important takeaways and one of the most important things that we do for these patients is we debulk their disease. So we try to reduce their disease, give them bridging chemotherapy or chemotherapy before CAR T to lower these numbers as much as we can to reduce the risk of immune mediated toxicities like neurologic toxicity. Can a prior neurological condition make someone more likely to experience delayed neurotoxicity? Certainly, patients who have history of neurologic illness like seizures, epilepsy, or even involvement by CNS myeloma, which is very rare, are at increased risk for developing neurologic toxicity. What should caregivers look out for when keeping an eye on patients for delayed neurotoxicity? It's a really good question. And I think the important thing to remember is that these are relatively rare toxicities and they differ a lot from patient to patient. So in that early phase after CAR T cell therapy, anything that looks a little off, you should give your team a call and let us decide if it's concerning for toxicity because it can look so different patient to patient. And that's why an important part of CAR T cell therapy is having a good monitoring plan in place for those early weeks. And so most centers that do CAR T cell therapy ask patients to be close to the CAR T cell center after the infusion. If you get a problem, we want you to call us. We don't want you to go to a different hospital or your primary care doctor. We want you to call us and we're going to be seeing you really frequently. Some of the things that we are watching for, obviously any weakness in the facial muscles, weakness in the eyes, that sometimes the symptom that comes from weakness in the eye muscles is sometimes double vision. And so patients will see double because their eyes can't move left and right together. That's the way they usually do. Watch patients who have difficulty speaking or any neurologic symptom, difficulty speaking or doing normal motor tasks or anything that any body part that is not moving the way it's supposed to. So I have mentioned my patient who had a difficult time raising his arm and putting on shirts and things like that. All of those are symptoms to be aware of. But like I said, really anything that doesn't seem right, you want to call your team because these toxicities can be subtle. And we think that if we detect them on the earlier side and try to intervene on the earlier side, maybe we have a better chance of turning them around. Understanding delayed neurotoxicity is an important part of preparing for CAR T therapy, both for patients and caregivers. By knowing what to watch for and when to seek help, you can feel more informed and empowered throughout the treatment journey. To continue learning, be sure to check out the other lessons in Health Tree's CAR T treatment course designed to guide you every step of the way.