Dr Maziarz provides an overview of adverse events with CAR T-cell therapies and approaches to managing toxicities.
Kami Maddocks, MD: We’d be remiss not to touch on the safety. You’ve made excellent points that the safety and comparison to allogeneic transplant is definitely improved. But can we talk a little about short- and long-term adverse effects of the approved CAR [chimeric antigen receptor] T-cell products?
Richard T. Maziarz, MD: Toxicity is always one of the things we fear for any new therapy. Safety and efficacy are the 2 factors that we want to identify when we pursue clinical trials. Ultimately, a third factor these days, as Dr Miklos was referring to, is cost. There’s safety, efficacy, and cost. As far as safety, CAR T initially had its own set of toxicities. Having been there from doing these studies for 7 or 8 years, I can recall having some of the early discussions with colleagues of mine across the country regarding when to decide to intervene on toxicity. I still remember that the comment was, “Somewhere between a 40% non-rebreather mask in this patient.” You don’t want to disrupt those cells. You want those cells to do the job.
When the study started, the early toxicity that was associated was what we now all identify as cytokine release syndrome [CRS]. It’s got an ICD-9 [International Classification of Diseases, Ninth Revision] label, and it’s even graded now with the ICD-9 coding, so everyone recognizes cytokine release syndrome. It’s an inflammatory binding, again, products of T cells. We think chronic or active inflammation is often associated with neutrophils, but now we’re defining it as a T-cell–based inflammatory event. Cytokine release syndrome is associated with vascular leak. As a consequence, it’s associated with hypotension, hypoxia, and fever.
There were several classifications for cytokine release syndrome early on, because a lot of the first centers—Memorial Sloan Kettering Cancer Center, Penn [University of Pennsylvania], and the NIH [National Institutes of Health]—developed their own classification for this toxicity. Fortunately, across the world, they’ve now adopted the American Society for Transplantation and Cellular Therapy [ASTCT]’s consensus definition of cytokine release syndrome. That’s a simple grading system that will allow an intervention to take place. The importance of that grading system is that not only does it identify a toxicity that requires an intervention, but it’s a communication. The most critical aspect and accomplishment of creating a language is that across the world, we’re now seeing presentations from Europe and Australia all adopting the ASTCT consensus guidelines.
But as CAR T extends to the community, there has been a lot of dialogue that this should never be done in the community because these patients are too sick and it’s too dangerous. Meanwhile, the community wants to treat with CAR T. This ASH [American Society of Hematology annual meeting] highlighted that the community will treat patients with CAR T-cell therapy, and having a language and a tool that will help guide the treatment is critical.
The first adverse event that we’re always worried about is cytokine release syndrome. That isn’t unique to CAR T. We’re now seeing and identifying it in the patients who receive blinatumomab, a bispecific antibody for treatment of ALL [acute lymphocytic leukemia]. When we give IL-2 [interleukin-2 therapy] to our patients with melanoma or renal cell carcinoma, they experience a cytokine release syndrome. Post-transplant with haploidentical transplant, where we release the T cells in the individual, is also associated with cytokine release syndrome. We have a new language. We have a toxicity that’s been there, but now we can share it and communicate it.
The next major toxicity that people worry about is neurotoxicity. This is a very interesting event. It’s associated with CAR T. It had a number of names early, but now it’s unified under the term ICANS[immune effector cell-associated neurotoxicity syndrome]. It’s associated with a vascular leak. It’s been questioned whether T cells see targeted antigens on the neurons or the glia. That was a work-up. There were data from the ROCKET study, the JCAR015 study, where there was early toxicity with cerebral edema. The early autopsies demonstrated there weren’t even cells in the brain, it was all vascular leak and endothelial injury. The neurobiology of neurotoxicity is still being unraveled. There’s some fantastic work coming out, but it’s linked to cytokines and vascular leak. Cerebral edema can be seen. It’s frightening the first or second time you see it. When someone becomes comatose within hours, you say, “What have I done?” But most of these patients recover.
We also now have a language that will help us grade the ICANS and communicate a treatment strategy, a grading system where potentially we’ll intervene with prophylactic antiseizure medicines. We’ll intervene with our current best therapy, which has been high-dose steroids. We’ve been using and seeing an emergence of new agents that will block the anti-inflammatory signal. These are the early toxicities associated with CAR T.
The other point that everyone is aware of is, when do we see these toxicities emerge? This was the issue, and Dr Miklos was saying, they all have the same target binding site. But the constructs are different, they use different activation domains. It appears that using a T-cell activation domain that’s designed to force rapid proliferation, which is the CD28 class of CARs, does have a faster onset of an inflammatory signal with both toxicities, CRS or ICANS. With ICANS, the lisocabtagene and tisagenlecleucel, which use the 4-1BB activation domain, is more associated with a later development of a toxicity profile, which gives a different timing.
This is now translating to practice, where patients are often treated with 4-1BB CARs in the outpatient setting, as long as you have the rapid ability to move a patient to an inpatient setting if they develop a toxicity. Many centers are still preferring to utilize the aggressive CD28 CARs in the inpatient setting because it can be within hours that a CAR T toxicity can emerge, and you might as well be ready for it and have your team in place. These are the short-term toxicities. We’ve talked about large cell lymphoma. We have the choice in mantle cell lymphoma and in adult ALL over the age of 25 the opportunity to use the 4-1BB–based CAR, which is tisagenleclecel, which has that FDA label.
Transcript edited for clarity.