Locoregional delivery of IL-13Ralpha2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.
Publication Year:
2024
PubMed ID:
38454126
Funding Grants:
Public Summary:
CAR T therapy is a new approach to improving the treatment of recurrent high-grade glioma, a type of brain cancer that is hard to treat with existing methods. This summary describes a completed early-stage (phase I) clinical trial that tested CAR T cells designed to target a protein called IL-13Rα2 in 65 patients with recurrent high-grade glioma, most of whom had recurrent glioblastoma (rGBM). The main goals were to check the safety and practicality of the treatment, find the best dose for future trials. Secondary goals included looking at patient survival, how the disease responded to the treatment, and changes in patients’ immune system tumor environment. The trial tested three ways of delivering the CAR T cells directly to the brain: into the tumor (ICT), into the brain's fluid-filled spaces (ICV), and a combination of both. It also tested two different ways of making the CAR T cells. The direct brain delivery methods were practical and generally safe, with no severe side effects limiting the dose. The most serious treatment-related side effects were one case of brain dysfunction (grade 3 encephalopathy) and one case of poor muscle coordination (grade 3 ataxia). Half of the patients (29 out of 58) experienced stable disease or better, with two showing partial tumor shrinkage, one showing complete tumor disappearance, and another showing complete disappearance after additional CAR T treatment outside the trial. For rGBM patients, the average survival time was 7.7 months, with those in the final part of the trial living an average of 10.2 months. The treatment was linked to increases immune activity, and higher levels of certain immune cells in the tumor before treatment were linked to better survival. These results suggest that this IL-13Rα2 CAR T therapy is safe and shows potential for helping some patients with this challenging type of brain cancer.
Scientific Abstract:
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Ralpha2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 x 10(6) CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNgamma, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Ralpha2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .