CAR T Therapy Effective for Numerous Hematologic Malignancies, Even in Heavily Pretreat Patients

Deepu Madduri, MD

Chimeric antigen receptor (CAR) T cells have proven an effective therapy for numerous hematological malignancies, even in patients who are heavily pretreated.

The FDA-approved CAR T-cell products include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), brexucabtagene autoleucel (Tecartus), tisagenlecleucel (Kymriah), axicabtagene ciloleucel, and (Yescarta). Together, these approved agents allow CAR T cells to be administered to specific patients with relapsed or refractory multiple myeloma, diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, relapsed/refractory mantle cell lymphoma, and acute lymphoblastic leukemia.

CAR T cells are generally safe, with the most common toxicities being cytokine release syndrome and neurotoxicity, according to Deepu Madduri, MD, an oncologist with Mount Sinai Health System. Younger patients tend to do better, however, older patients should also be considered for the therapy. Additionally, patients who are CAR T eligible should consider the process as soon as possible.

CAR T cell therapy is also being explored in solid tumors. Recently, fast track designation was granted to a CAR T cell therapy for the treatment of thyroid cancer and research around the efficacy of CAR T cells in brain tumorsis currently underway.

In an interview with Targeted Oncology, Madduri discussed the need for further CAR T-cell therapy research, expanding it into other hematology malignancies. She also discussd management of the common adverse events associated with CAR T cells.

TARGETED ONCOLOGY: Can you start off by speaking to the mechanism of action for CAR T-cell therapy? Are there any notable differences between first, second, and third generation products?

CAR T stands for chimeric antigen receptor. They are T cells that are re-engineered and there are multiple generations. With a second-generation agents, there's either co stimulatory domain of CD28 or 4-1BB, and then the third-generation agents are modifying it. The point of that is to make sure we have a CAR T therapy that is less toxic, but actually persists and causes more efficacy. CAR T cell is when you take the T cells, you re engineer it, you modify it in a way that it recognizes the antigen on the tumor cell. This helps when we reinfuse the patient. The patient gets lymphodepletion, then we wipe out the T cells that they have, and we reinfuse them with these CAR T cells. When they go into the body, they expand, they proliferate, they attach to the tumor antigen and cause slices and cause the side effects that we had talked about, which is mostly cytokine release syndrome.

Can you touch on some of these toxicities that we've seen associated with CAR T-cell therapy and just how they're being managed on a more clinical level?

One of the most common CAR T complications is cytokine release syndrome. We also have neurotoxicity, which is another possibility. We see that more with the CD19 CARS than we do as much as the BCMA CARS, not that it doesn't exist. But the most common complication is cytokine release syndrome, which is when the patient develops a fever, and they have either hypoxia hypotension, or they could just have fever for an extended period of time. The way we typically manage these are with tocilizumab, which is approved now for CRS management. It's an IL-6 receptor antibody that we use to block one of the cytokines that we know is produced during this cytokine release syndrome cascade, which is particularly IL-6. And often patients when they get infused with tocilizumab, within 4 to 6hours, you'll see that they feel a lot better their fever may have resolved. and if these patients continue to have fever or they started having neurological complications, we add steroids, that's the next line of treatment. So usually it's dexamethasone (Ozurdex) 10 milligrams IV every 6 hours. Other agents that we also consider adding depending on the level of CRS one, is anakinra. Some other drugs we can give is siltuximab (Sylvant) And if the cytokine release syndrome is really bad and we just want to stop the whole thing from happening, we can escalate the dose of the steroids or sometimes even give the low dose Cytoxan that we usually given lymphodepletion to help the whole critique process.

What are some methods for detecting early neurotoxicity?

One of the things that we implemented is using a daily sentence. So, we actually have our patients write a daily sentence every day on the same piece of paper or a book that we give them. They choose whatever sentence it is, and we have them write it every day. One of our patients that had neurotoxicity, we clearly saw right before he had clear signs of neurotoxicity, he wasn't able to write the sentence properly. He wrote the same word twice and was unable to spell out the words that he could. So, we think that doing an immune effector cell-associated neurotoxicitysyndrome (ICANS) score, and ICANS score that we usually typically do like the CAR T cell-therapy-associated toxicity (CARTOX)-10 is what we used to use before where we ask them their name, their age, and other criteria. What we found is the patients do it so often, they memorize the answers. So, if you're asking the same three objects or saying whatever they remember. But doing this kind of gives us an idea of early detection.

CAR T-cell therapy has shown some great efficacy in a couple of different hematologic malignancies. Can you touch on some of the results that we've seen in acute lymphoblastic leukemia and non-Hodgkin lymphoma (NHL) spaces?

In ALL, we have Kymriah that we can give in patients who are under 25 years and are who relapsed/refractory or in their second relapse. We've seen good overall response rates of 81% and the 24-month RFS was 62%. We also saw that we did see some neurotoxicity associated with it, but grade 3 or higher was only 13%, which is pretty good. With CRS, we saw mostly grade 1 and 2 CRS with about 49% grade 3 or higher. In terms from NHL, we have Kymriah. Then we also have another agent approved for MCL. Kymriah is currently being investigated for NHL, and we have Yescarta that we can also use for patients with DLBCL. Both of these are pretty good overall response rates of 93%, 83% for Yescarta.

Overall, from what we've seen with the lymphoma studies, we're seeing really good response rates for 1 time treatment for these patients who are heavily pretreated. We're also learning a lot when we extrapolate them to BCMA studies, and these studies show low-grade toxicities, particularly CRS or neurotoxicity.

How do you decide which patients are best suited to receive CAR T-cell therapy? What kind of factors are you taking into consideration?

I think one of the things we look at when we're looking at who the best fit for the patient is efficacy. If there's a lot of different trials, they're all targeting the same agent, particularly in myeloma, the BCMA landscape is quite saturated. We're going to have to look at efficacy when it comes down to if you have 3 products, and you're going to try to pick between the 3 what one is better. But at this time, a lot of the studies are too early, and we don't have enough data to really cross compare one study versus the other. So, we actually just look at the patient in themselves. If they're even a good candidate for CAR T, one of the things we look at is their age. Age is just a number, but I've taken an 82-year-old to CAR T and they did perfectly fine. But, we want to make sure somebody doesn't have too many comorbid conditions and they have good performance status. Also, we want to look at their disease progression. So, if there's somebody who's progressing quickly, then they wouldn't be the best candidate to go to CAR Therapy where it takes anywhere from 3 to 5 weeks to manufacture their cells. So ideally, we'd want a patient where we know that we can control their disease with some bridging chemotherapy. We know that they're not going to progress and not make it to the CAR T anywhere from 3 to 4 weeks later. 

Within that same vein, are there future research efforts that you feel need to be made in order to kind of progress CAR T products forward?

Yes. I think one of the things that we need to do is understand CAR T-cell resistance a little bit and also understand why CAR T cells are not persistent in some people, and is persistence that important for the efficacy? We've seen some products, maybe CAR T cells are gone by 2 months and some products, they're there for 6 months. We have BB21217, which is a sister product for the ide-cel where they're incubating the T cells with PI3 kinase hoping for these T cells to last longer. And we're waiting to read out the efficacy from this study. [The question is] does that mean that they're going to have longer PFS? So, there's a lot about CAR T that we don't know.

I think one of the really key important things is, especially for the community oncologists, is early referral. It's important for us to know about the patient when they're on their second- or third-line therapy and they're having stable disease or you know that they're about to start progressing. This allows you to know when to get them enrolled into a CAR T-cell clinical trial, get them to an academic center, and get them screened.