IL18-Armored CAR T-Cell Therapy Produces Deep and Sustained Responses for Heavily Pretreated B-Cell Acute Lymphoblastic Leukemia
Key Clinical Summary
- Population and Design: Phase 1, single-center study evaluated a fourth-generation IL18-secreting CD19-directed CAR T-cell (humanized scFv; expedited 3-day manufacturing) in 5 heavily pretreated adults with R/R B-ALL (median 5 prior lines; post–allo-HCT and post–prior CAR-T allowed).
- Efficacy: At 3 months post-infusion, ORR 100% with CR 80%; all MRD-evaluable patients achieved MRD-negative CR, and a CNS-only case achieved complete CNS remission. With median follow-up 19.6 months, no relapses or deaths were observed; some patients demonstrated long-term CAR persistence in blood/CSF, and successful retreatment-maintained remission.
- Safety: CRS occurred in all patients but was ≤ grade 2; ICANS in 2/5 (one grade 3 in a patient with extensive baseline CNS disease). No unexpected toxicities, no treatment-related deaths, and no IEC-HLH–like syndrome were reported.
- Clinical Relevance: IL18-armored CD19 CAR T-cells were feasible, tolerable, and highly active, producing deep, durable remissions in R/R B-ALL, supporting expansion to larger cohorts for further evaluation.
Matthew Connor, MD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, presented early results from a phase 1 trial of IL18-armored, CD19-targeted CAR T cells among heavily pretreated adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida.
All 5 treated patients achieved responses, including 80% complete remissions and a manageable safety profile limited to low-grade CRS and infrequent ICANS.
Dr Connor concluded, “these IL18-armored CAR-T cells for relapsed/refractory adults with B-ALL were safe and feasible to produce.”
He added, “Thus, the next steps are to expand this novel CAR construct to treat more patients.”
Transcript:
My name is Matt Connor. I'm an assistant professor at the University of Pennsylvania and I'm here at ASH 2025. I'm here to discuss my presentation of our group's phase 1 trial of IL18-armored CD19-targeted CAR T-cells for relapsed and refractory B-ALL.
This is a phase 1 trial for patients with relapsed disease using a novel CAR construct of an IL18-secreting CAR T-cell, 4th generation CAR, that has a humanized single chain variable fragment and is also manufactured in an expedited 3-day process. We treated patients who were relapsed in their second or later relapse or after allo transplant, as well as patients who had primary refractory disease.
In this small study, we enrolled 5 patients with no screening failures and produced products for all 5 patients successfully prior to treatment. The patients were heavily pretreated with a median of 5 lines of prior therapy. They're median aged 41 years old and 3 patients had Philadelphia chromosome-positive disease. Four patients had relapsed after prior allo transplant and 2 patients after prior commercially available CART-19 products.
In safety evaluation, patients didn't experience any unexpected toxicities, no treatment related deaths. The cytokine release syndrome incidence was 100%, so all patients had CRS, but no higher than grade 2 disease. So 2 of the 5 patients experienced ICANS, 1 peaking at grade 3, although notably this was a patient with extensive CNS disease at enrollment. No other pertinent safety signals were seen with no immune effector cell mediated HLH-like syndrome.
For our preliminary efficacy evaluation at month 3 post-infusion, we had 100% overall response rate with 80% complete remissions. All patients evaluable for measurable residual disease achieved MRD negative complete remissions. One patient who was not evaluable had CNS only disease and achieved complete CNS remission. We're at 19.6 months median follow-up at this point, and all patients remain in complete remission with no relapses and no deaths on study.
In our correlative data, we've seen that a subset of patients has long-term persistence of their CAR T-cells in the CSF and peripheral blood. Although some patients did lose aplasia of B-cells, 2 patients were retreated with the same product on study, and both remain in remission at last follow-up.
In conclusion, these IL18-armored CAR-T cells for relapsed/refractory adults with B-ALL were safe and feasible to produce. They produced encouraging results in terms of early deep remissions, and there have been no relapses or deaths on study as of yet, and they have a similar toxicity profile to commercially available products. Thus, the next steps are to expand this novel CAR construct to treat more patients.
Source:
Connor M, Hwang WT, Gill S, et al. IL18-armored CAR T Cells in Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia. Dec 6-9, 2025; Orlando, FL. Abstract: 812
