Stephen Bagley, MD, University of Pennsylvania, Philadelphia, Pennsylvania, discusses results from a phase 1 dose-exploration study which assessed intracerebroventricular (ICV) delivery of CART-EGFR-IL13Rα2 among patients with recurrent glioblastoma. Results showed that this delivery of CART-EGFR-IL13Rα2 demonstrates clinical promise in this patient population. 

These data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hi, I am Steven Bagley, neuro-oncologist at the University of Pennsylvania, and Section Chief of Neuro-Oncology, and I presented this morning at ASCO 2025 the results of our phase 1 clinical trial of a bivalent dual targeting CAR T-cell product for patients with recurrent glioblastoma. 

This work builds on our previous clinical trial, which was done last year and was published as a 6-patient interim report in Nature Medicine and we were excited that we were seeing tumors shrink initially, which we don't see very much in glioblastoma, but it wasn't clear how long that was going to last and how many other patients might experience similar shrinkage. Since then we expanded the study, we've now treated a total of 18 patients and the patients were treated across 3 different dose levels: 6 patients received 5 million CAR T-cells, that was our de-escalated dose level –1, we treated 6 patients at 10 million cells, which was dose level 1, and we treated 6 patients at 25 million cells, which was the highest dose level, dose level 2. 

What we observed in terms of toxicity was that all of our patients get fevers, which we give as grade 1 cytokine release syndrome. A small percentage of patients did have grade 2 cytokine release syndrome, but mainly what we see are fevers that are largely neuroinflammatory in nature. We also see neurotoxicity in all of the patients, 100% of patients out of the 18 experienced some degree of neurotoxicity. In about half of those patients, it was actually grade 3 in severity, the others were grade 1-to-2. That neurotoxicity clinically has a flavor that is somewhat like ICANS [immune effector cell-associated neurotoxicity syndrome], which is well described in patients with CAR T-cells for leukemia and lymphoma, but there's also a bit of a different element that is much more acute. The onset is typically within 24 hours, and it's related to peritumoral edema and inflammation, and this is well characterized now as something called tumor inflammation associated neurotoxicity or TIAN, so we saw definitely elements of both. The good news is that this is generally reversible, manageable, we sometimes have to use corticosteroids, sometimes we use anakinra, but at the end of the day, patients generally turn around in 48 to 72 hours after the cell dose. That was the toxicity profile in a nutshell. 

What we observed also with regard to the dose level and the CAR T-cell expansion was that 25 million cells, which was our highest dose level, clearly performed best and we saw highest expansion of the CAR T-cells in the spinal fluid at this dose level. We also saw better persistence of the CAR T-cells, so they'd last longer at the higher dose level. 

People are generally pretty excited about the efficacy results, which is that we see the tumors shrink in a pretty high percentage of patients. Out of the 13 folks who had measurable tumors at the time of the infusion, we saw the tumors shrink in 8 of those patients, or 62%. That rate of tumor shrinkage is really remarkable again, because we don't tend to see that with immunotherapies of other types in glioblastoma. In terms of durability, most of the patient's responses don't last very long. We see that most patients relapse around 2 or 3 months into the CAR T-cell product. We do have 1 patient who is a super-responder who actually came into the trial with leptomeningeal disease, which carries a typical prognosis of about 8 to 12 weeks, and he's actually still alive and well, now 22 months after the initial infusion and he experienced a 20% reduction in his tumor that's been long-lasting and ongoing since that time, so sort of a case example of the potential of the therapy, but we certainly have a lot more work to do. We have to identify mechanisms of resistance, we have to potentially make some engineering changes to the product, and eventually different drug combinations to make this work better and longer but I think we're on the right track and we're all excited about next steps. 

In terms of future clinical trials, we have one ongoing right now where we're giving the same product to recurrent glioblastoma patients, but with repeated doses so 2 doses separated by 14 days and then we also have a newly-diagnosed clinical trial that's giving the same product to newly-diagnosed patients after they complete standard radiotherapy, we'll be administering the CAR T-cell product as a maintenance therapy to try to prevent the recurrence in the first place, so these are the next directions and we look forward to what we find.

Source: 

Bagley S, Binder Z, Fraietta J, et al. A phase 1 study of intracerebroventricular (ICV) delivery of bivalent chimeric antigen receptor (CAR) T-cells targeting EGFR and IL13Ra2 in patients with recurrent glioblastoma (rGBM). Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract 102