Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial
Mené sur 18 patients atteints d'un glioblastome récidivant, cet essai de phase I détermine la dose maximale tolérée d'une immunothérapie intra-cérébroventriculaire à base de lymphocytes CAR-T ciblant EGFR et IL-13Rα2 puis évalue son efficacité du point de vue du taux de réponse objective et de la durée de la réponse
Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12–15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13Rα2), or CART-EGFR-IL13Rα2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13Rα2 cells. The maximum tolerated dose was determined to be 2.5 × 107 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity; none had grade 4–5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%; 90% confidence interval, 0–32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1–3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13Rα2 is feasible and appears safe. CART-EGFR-IL13Rα2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. ClinicalTrials.gov registration: NCT05168423.
Nature Medicine , résumé, 2025