What neurotoxicities are associated with T-cell therapies? How are these toxicities managed? What is the risk of delayed toxicity?

What neurotoxicities are associated with T cell therapies? How are these toxicities managed? What is the risk of delayed toxicity? So both CAR T cell therapy and bi-specific T cell engagers can be associated with neurotoxicity, which are toxicities to the nervous system. I think myeloma patients have to realize that a lot of those terms and a lot of the concern around this was really framed when CAR T start being developed mostly in other diseases, particularly leukemia and lymphoma, where those complications seems to be quite a bit more frequent. When I like to think of T cell redirecting therapies like CAR T or bi-specific antibody I like to think about neurotoxicity in two ways. One, the acute setting, which is really the first couple weeks to a month after starting the therapy, and then delayed neurotoxicities, which may happen after that initial time frame. In the acute setting, we have a patient be observed fairly closely to monitor for something called ICANs, which stands for immune effector cell associated neurotoxicity syndrome. It's a mouthful and it really encompasses a lot of different things that could happen, but we know that the inflammation that's associated with these T cell redirecting therapies, while hopefully killing myeloma cells, can cause negative impacts on the brain. One type is something they call ICANs, or immune effector cell associated neurotoxicity syndrome. And honestly, there's not a great understanding of how it happens. We believe it's some of those inflammatory substances in the body that we call cytokines that are part of the immune response that a CAR T or the bi-specific trigger can transfer themselves into the brain and the tissue surrounding the brain and cause those symptoms. But it manifests primarily as confusion, and in some cases the person being unable to formulate words. The way that often may first manifest initially is what we call expressive aphasia. Difficulty with speech, maybe thinking you know what you want to say, but the words are coming out slowly or not coming out much at all. Other things that might be a first sign of it is tremor, so if you notice shaking of the hand or foot that's out of the ordinary. Issues with attention, just not being able to pay attention or count backwards, things you would normally be able to do. Changes in handwriting is something we often notice early on, and so when people are being observed after CAR T cell therapy, we often do a handwriting assessment once or twice a day to monitor for that. If those toxicities, that type of neurotoxicity called ICANs becomes more severe, it can lead to things like seizures or kind of swelling of the brain, which can make a patient very sick and unresponsive. We monitor for that closely. There are some tools that we use to monitor and grade, including something called ISA score, which is essentially a bunch of questions that are apparently silly for somebody who is in the right state of mind, but when you are over, under that syndrome, you might struggle with like basic math, recollections, naming objects and so forth. As you know, for every side effect of any treatment, we have kind of a grading scale, right, which I don't need to bother you to memorize in that, but long story short, we talk grade one and grade two are the things that are trivial, they get better quickly, they're not life-threatening. Grade three requires more attention, more intervention. Grade four is life-threatening. The ICANs in CAR T cell therapy for myeloma is rare, less than 10% of the time, and almost always grade one and grade two. It's an absolute exception that somebody would have a higher grade of ICANs, and the management of that is usually corticosteroids, you know, a few days of dexamethasone, and people usually turn around very quickly. At this point, we don't know, and there's really, there's not a lot of reason to believe there will be any long-term effect of having experienced that neurotoxicity, which is usually for a couple of days. So we do our best to intervene on these neurotoxicities early on to try to prevent those things, and those interventions for acute neurotoxicity is usually steroids, so the treatment of ICANs is steroids up front, and if escalating doses of steroids are not working, there are other anti-inflammatory drugs that we can add to try to improve that. Certainly, if a patient does develop seizures, we get our neurology colleagues to help us with medicines to try to improve those things. When we talk about delayed neurotoxicity, this has really been seen mostly with CAR not as much with bi-specific antibody therapies. Relatively rare, but still something that can occur and something to be aware of, because it can happen at any time after. And so the ones that we consider the most concerning are abbreviated MNTs, or movement and neurocognitive toxicities, and that really kind of presents itself very similarly to Parkinson's disease. It's not quite the same pathophysiology, but it's very similar. So what changes might you notice? A resting tremor, so tremor in the hands when you're not doing anything with your hands. Changes in facial expression, so reduced amount of facial expression, personality changes. Changes in the ability to walk well, so usually slower, slower to get up, slower to take steps. Those are all things that could be a sign of these delayed neurotoxicities, such as MNTs. There are some other things that can happen later, like peripheral neuropathy, which is like numbness or tingling in the nerve, which is most often in the hands or feet. We see that with a lot of therapies in myeloma, but certainly has been detected after these T-cell redirecting therapies. And then additionally, some patients after CAR T have been noted to have what we call cranial nerve palsies, most commonly Bell's palsy. So that's when the nerve that supplies the face muscles gets paralyzed temporarily, so patients may notice a facial droop on one side or difficulty closing an eye, which can cause the eye to become dry. Those are all potential late neurotoxicities associated with these therapies. Now the incidence of that is low, about 10%, roughly speaking. It appears to be more common with one of the CAR T's available called Silt-to-cell. Most of those symptoms tend to get better over time, but at this point, there's not a very well described long-term natural history. We do a lot of things, particularly high-dose steroids, trying to mitigate those symptoms, but it's a little bit unclear whether they really have any influence. So the more rare movement in neurocognitive toxicities, the MNTs, how to best manage these is still somewhat being investigated. We usually get our neurology colleagues involved to help and often try immunosuppressive therapies upfront, things like steroids, potentially IVIG. Medicines that are used to treat Parkinson's like Carbidopa, Levodopa have been tried with relatively limited success. One thing that we know about neurotoxicity and about toxicity in general, it tends to be worse and higher and longer lasting. The more disease the patient has in when the CAR T is administered, which kind of makes sense because this is coming from a byproduct of the engagement of the immune system. Recently there's been a couple case reports because these toxicities seem to be associated of CAR T cell in the blood and long persistence of the CAR T cell. If that toxicity is severe, we can make the decision to try to give a high dose of chemotherapy to try to kill the remaining CAR T cells and improve the side effect, which is usually kind of the last resort effort if the side effect is severe enough. For things like peripheral neuropathy, they're managed relatively conservatively like they would be with other drugs. Sometimes if it's in the CAR T or T cell therapies, we can try some steroids, but otherwise if a patient has like a burning pain related with their neuropathy, we can try medicines to help with that like gabapentin or deloxetine. We've kind of noticed both patterns. They do tend to persist longer than the acute neurotoxicities, than the ICANS. In some of the clinical trials, some patients have had a resolution of those side effects, thankfully within the subsequent weeks or months, but unfortunately in some cases they have persisted longer. One other thing to note about these MNTs or movement in neurocognitive toxicities, it seems to happen more frequently with Cilta cell or CARVICTI, which we kind of think of as our more potent CAR T cell. Although it has been noted with the other approved CAR T cell, IDA cell or ABEKMA as well. One hopefully beneficial thing is now that we have the ability to give CAR T in earlier lines of therapy. What they noticed on the original study when about 5% or 6% of patients developed these toxicities is that they were more likely to have them if the myeloma was not under good control going into the Cilta cell or the CARVICTI. When they did the study in earlier lines of therapy, when the patient's myeloma was refractory to less treatments and thus bridging therapy could be more effective at keeping the disease under control going into CAR T, they noticed a nice reduction in the incidence of those side effects. Only about 1% of patients were noted to have these MNTs in the CARTITUDE 4 study, compared to I think 6% when it was studied in later lines of therapy. Being able to control the myeloma better prior to the CAR T and also earlier and more aggressive management of things like cytokine release syndrome and ICANS, we can hopefully continue to reduce the frequency of these side effects and the severity of them. I think as we move CAR T cell therapy to earlier lines and we learn better to handle the disease leading to CAR T cell therapy, we're likely that this is going to become a lot less common. Now in terms of bispecifics, because bispecifics were developed and studied after CAR T and the mechanism of action is somewhat similar, at the end of the day you engage in T cells into fighting the cancer, a lot of the practices and terms and nomenclature got carried over, including the notion of ICANS. But the reality is that is far less common. We talk about less than 5% in general, almost never grade 3. And in some bispecifics being approved or under study is essentially zero. So I would say it's almost a no issue in bispecifics and those long-terms no ICANS toxicity have really not been described with exceptionally perhaps some worsening of peripheral neuropathy.