Ongoing Issues in CAR T-Cell Therapy and Lymphoma

Stephen J. Schuster, MD: What I want to hear about is patients with central nervous system disease when we were developing C19-directed CAR T cells. What’s your experience with CNS?

Matthew J. Frigault, MD: It’s extranodal relapse of disease that happens to be in the CNS. A lot of groups are starting to look at this. There were some data presented at ASH from The University of Texas MD Anderson Cancer Center of using axi-cel for patients who had a history of or active CNS disease. I know there are trials that are currently in development for both secondary and primary. But overall, we assume the risk factors for CRS and neurotoxicity are more derived not so much from the T cells, but from the innate immune activation and inflammatory cascade that comes thereafter. Theoretically, the patients with secondary and primary CNS should be at lower risk, given lower disease burden and less immune inflammatory priming in the systemic circulation. What we’ve seen, at least the first 8 patients whose results we published, was about 50% overall response rate, 3 of whom are still alive and in CR today. We’ve got about 30 in total we treated, and we’ll be putting that series together. They’ve actually started treating primary CNS lymphoma on an investigator-initiated trial, and we’ve got about 4 patients accrued. We’ll have those data available for this year. Overall, the biggest issue with systemic lymphoma…is getting the patient safely to the therapy, meaning that they’re not progressing too rapidly. Their disease should be under control. Going back to, I think, prior points that Caron, Loretta, and everyone else made was that steroids in these patients, if you need them, you give them, and it doesn’t necessarily have that deleterious of an effect.

Stephen J. Schuster, MD: Yes, I did read your paper, Matt. And you say so nonchalantly, it’s another extranodal site, the brain. But those patients of yours, these were not extra-axial CNS lesions. These people, they had parenchymal extranodal brain lesions. I would have expected more toxicity than you observe. But like I said, I’ve certainly been wrong before.

Matthew J. Frigault, MD: Anecdotally, the toxicity you can see is there, I’m not going to say pseudo-progression, but a little bit of inflammation in the critical part of the brain can cause a lot of problems. And I think that’s where I don’t want people to run off and start giving everybody CAR T cells for secondary CNS. Disease control going into the actual therapy is the most critical component, because if you lose control midtherapy, it doesn’t matter if the patient responds in 4 weeks; they’re not going to be alive in 2.

Stephen J. Schuster, MD: That disease control also underlies the success of CAR T-cell outcomes in systemic lymphoma therapies, as well. And I think David’s going to have a blood test for disease control soon. The CT DNA.

David Miklos, MD: Matt, the products that you reported on was tisa[-cel], right?

Matthew J. Frigault, MD: Correct.

David Miklos, MD: We may have different results using different agents. I know, Caron, you’ve been working on some of that as well. I want to throw out 1 other unmet need that I think we all want to push for as well, and that is patients with HIV. HIV and lymphoma have been a problem. Because of CD4 attacking they are more at risk for the lymphoma in the first place, they’re not necessarily going to be good autologous CAR T-cell donors. I mean, we can talk about it. We can argue about it. This is a place where allogeneic CAR T cell holds some promise. These patients are eligible for that study that was just presented. I encourage you to consider that when referring your patients with HIV to the Allogene sites. I’m bringing 1 on right now.

Stephen J. Schuster, MD: It’s certainly not something that is excluded by the label or included in the label. But Kite has a standard operating procedure and will manufacture autologous CAR T cells for HIV-positive patients. And we’re doing that. But Novartis doesn’t, and so you can’t do tisagenlecleucel.

David Miklos, MD: Steve, I’ve also made CAR T-cell products for patients with HIV. Unfortunately, the 2 patients didn’t do well. One never got to the therapy with massive disease progression.

Matthew J. Frigault, MD: We’ve treated and publishedresults on 2, both of which are in CR.

Stephen J. Schuster, MD: And because of your publication, Matt, we’re now doing it, too. Again, maybe enough of this gets done. Somebody’s going to have to put a series together.

Matthew J. Frigault, MD: This is going to be a big component, just to make a plug for regulatory. A lot of the reasons why patients aren’t being treated is based on how the products were approved and the regulatory hoops that people had to jump through for the manufacturing process. For populations such as this, I would ask the FDA and other regulatory bodies to help expedite getting access to patients, because biologically, it makes sense that we’re not manufacturing for them.

Transcript Edited for Clarity