Exploring Barriers to CAR T-Cell Therapy in Blood Cancer Patients | Yannis Valtis, MD | #ASH24

Hi, my name is Yannis Valtis. I'm a fellow at Memorial Sloan Kettering Cancer Center in New York City. Thank you so much for inviting me to chat. So this is an abstract that looks at the barriers to CAR T-cell therapy for patients with hematologic malignancies, so blood cancers. So as many of you probably know, CAR T-cells are one of the new very exciting ways of treating blood cancers. They are engineered T-cells. We take the T-cells that are part of the patient's immune system, and then we engineer them to attack the cancer cells. And we've had very good successes in both lymphoma and myeloma, as well as some leukemias. The reason why we wanted to look at this particular question and present this abstract is because not everyone that would like to get a CAR T-cell is ultimately able to for various reasons. And so we wanted to understand why that happens. So essentially what we did is we looked at our own referral cohort at Memorial Sloan Kettering Cancer Center, which is a big cancer center in New York City. So we looked at everyone that was referred to get a CAR T-cell, and then we followed those patients to figure out how many of them actually got a CAR T-cell, and then if they didn't get a CAR T-cell, why that was the case. So we were able to look at 400 patients that were referred to us from 2021 to 2023. About half of them were referred for lymphoma. The other half were myeloma and some leukemias. And one of the things we noticed is that the patients with lymphoma were coming in a little earlier, so they had fewer treatment lines than the patients with myeloma that were coming in with more lines of treatment. So of the 400 patients that were referred, 177 or 44% of them ultimately did not get a CAR T-cell. And that's a higher number than we anticipated. If you look at some of the clinical trials that were done, about 10 to 20% of those enrolled in a clinical trial for a CAR T-cell end up not getting it. And so in the real world, we found a higher number of 44% of patients not getting the CAR T-cell. So then of course we asked, okay, what are the reasons why people are not getting a CAR T-cell? And the biggest reasons were the first one was rapid disease progression, which means that once cancer is actually behaving aggressively and we need to use another treatment such as chemotherapy to control it, one of the problems with CAR T-cells is that they do take a while to manufacture. So in order to get a CAR T-cell, first you have to come in and get leukophoresis. So we collect your T-cells and then we send them to a lab and that process can take up to six weeks. And so for people whose cancer is moving really aggressively, CAR T-cell might not be a great option. And so about 20% of the people in our cohort that didn't get CAR T-cell was for that reason. Other things that came up was that patients, some patients were coming in without many lines of treatment and the FDA approvals for CAR T-cells specify how many lines of treatment one must have received. And so those people were not able to get a commercial CAR T-cell and they could only be considered for a clinical trial. And there was a number for whom we did not have a clinical trial available and so that's why they didn't get their CAR T-cell. And then we also found that there was a substantial number of patients where there were concerns for toxicity. And so the worry was that they would have too many side effects with a CAR T-cell. And so because of that, either the patients chose or their doctors together chose not to proceed with that treatment. And then a couple of other things we looked at, one was any associations between patient characteristics and likelihood of getting the CAR T-cell. And one thing we noticed was that black patients were less likely to get the CAR T-cell after getting referred to our center. And then we looked at, okay, why was that and were there any differences in the reasons why black patients compared to white patients didn't get CAR T-cells. We found that there was a higher proportion of black patients that came in with rapid disease progression and so their cancer was very aggressive or unable to do it. There was also a number of black patients that actually came when their cancer was very well controlled and complete remission. And so they didn't really need the CAR T-cell and so there was no point proceeding with that treatment. And then a couple of other things we looked at, we looked at people's survival and we found that the ones that didn't get a CAR T-cell because their disease was progressing so rapidly, unfortunately didn't do very well and many of them died quite early. And so putting all of this together, we then asked ourselves like, okay, what are some of the solutions that we might be able to think of in order to address these problems? So as I mentioned, rapid disease progression seemed to be one of the biggest problems and one of the biggest reasons. And so a couple of things to say to that. One is probably that early referral is really, really helpful here. So if a patient might benefit from a CAR T-cell with lymphoma or myeloma, it's a really good idea to refer that patient to a CAR T-center early so that they can be evaluated and the process can be set in motion so that if and when they need it, then we can deliver that to them rapidly. The other thing is that there are companies that are working on experimental CAR T-cells that are off the shelf and so they don't require that lengthy manufacturing process. And so if some of those CAR T-cells are shown in clinical trials to be efficacious and safe, then we might be able to use them for patients whose disease is progressing more rapidly. And then a couple of other things for the concern for toxicity. We need to keep working on making CAR T-cells safer. That might be through making the CAR T-cell itself safer or through coming up with strategies to give additional medications to lessen the toxicities. And then lastly, there was a number of patients who were not able to get a CAR T-cell because of logistical reasons. One of them is that currently the FDA mandates through a REMS requirement that patients stay in the vicinity of the CAR T-center for four weeks. And that can be a barrier for many patients. And so it's important to work with the FDA to see if that requirement still makes sense or if there's any changes that need to be made to it, given that we know that most people that are going to have any side effects from CAR T-cells usually have them within the first two weeks. I think it's a really important question. One thing that I think I should say and is important to say is that when Morris-Lyn Kettering is located in Manhattan in New York City, and so the patient population we see is probably not representative of the rest of the country. And so I guess I would say the first step is to continue looking at these types of questions and especially with a lens towards racial inequities across other centers and across other settings to see if they're true in other places or if this just happens to be a thing that are specific to our center. I guess I will say more broadly, because of structural racism in this country, there certainly is a history of black patients not getting the access they need to lifesaving treatments. And so I think we all need to just continue studying this and looking at what are the reasons why black patients might not get the access they need. As I said, in our study, there was a number of black patients that seemed to have been referred possibly too late because they had rapid disease progression, but then there was also a higher proportion of black patients that were referred when their cancer was actually in very good control and so they didn't need the CAR T-cell. So that could actually skew the results a little bit. So one of them is that because we will be able to treat people more quickly, we will not lose patients in that waiting period. So currently there is a waiting period of let's say four to six weeks between when the patient receives their leukophoresis, when the CAR T-cells are removed, until the time that they're delivered back. And so there are unfortunately a number of patients who died during that period and they just don't make it to be able to get the CAR T-cell. And so if we're able to shorten the manufacturing period, then we wouldn't lose those patients and maybe they could benefit from the CAR T-cell. And then in terms of safety, unfortunately there is still a number of patients who die of the treatment itself. So not even of the cancer, but just the treatment has such severe side effects that some people die of the treatment itself. And that's a relatively low number, but it's definitely not zero. And so as we make our CAR T-cell products safer, hopefully we will be able to drive that number to very close to zero. I think that it is a very exciting time where CAR T-cells are improving the outcomes of our patients. I think what I would say in general is, you know, I always encourage my patients to ask about clinical trials because clinical trials are A, how we learn and how we get better at doing what we're doing, but also are an opportunity to get access to therapies that might be better than the standard of care. It's important to say that we don't know if they're better than the standard of care, and that's exactly why we're doing a clinical trial. But I always encourage my patients to ask about clinical trials, to ask me and their other physicians, because sometimes those might be available and they might be able to help them.