Safety and efficacy of B7H3/IL13Rα2 bispecific armored CAR-T for treatment of recurrent/refractory glioblastoma.

e14062 Background: Recurrent/refractory glioblastoma (GBM) carries an extremely poor prognosis with limited therapeutic options. CAR-T therapy represents an innovative strategy for GBM, yet monospecific, single-infusion CAR-T is hindered by tumor antigen escape and inadequate efficacy durability. To address these two key challenges, we developed a fully human bispecific armored CAR-T targeting B7H3/IL13Rα2 and adopted a pharmacokinetic (PK)-guided precision multiple-infusion regimen to enhance efficacy and durability. Methods: This investigator-initiated first-in-human study adopted a 3+3 dose-escalation design, with four dose levels: 2.5, 5.0, 10, and 20 million cells. Eligible patients were 18-75 years old with recurrent/refractory GBM, confirmed by immunohistochemistry (IHC) to have ≥30% expression of both B7H3 and IL13Rα2. Administration was via intracavity/intraventricular Ommaya catheter, with serial cerebrospinal fluid (CSF) and peripheral blood CAR-T PK monitoring (CAR-T qPCR levels, flow cytometry subsets, and cytokines) guiding personalized dosing frequency. The primary objective was safety, and secondary objective was preliminary tumor response assessed by RANO2.0 criteria. Results: Two patients with IDH-wildtype, MGMT-unmethylated recurrent GBM completed low-dose (2.5 million cells) CAR-T infusions: the first received 4 doses, and the second 2 doses. No dose-limiting toxicities (DLT) occurred; adverse events (AEs) mainly included fatigue, thrombocytopenia, abnormal liver function, and hypoalbuminemia, all manageable with supportive care without ICU admission. Cytokine release syndrome (CRS) was grade 1 at maximum, resolving spontaneously within 3-5 days. Abundant central memory T cells were detected in CSF, and high CAR-T copy numbers persisted for ≥3 weeks post-infusion, demonstrating favorable durability. Best overall response: the first patient achieved ≥30% tumor reduction determined by RANO2.0 criteria with no progression during 3-month follow-up; the second maintained stable disease (SD). Conclusions: B7H3/IL13Rα2 bispecific CAR-T exhibits favorable safety in recurrent/refractory GBM: Low-dose, PK-guided multiple infusions avoided DLT, with all AEs reversible via standard interventions. It also demonstrates robust in vivo expansion and persistence, supporting subsequent dose-escalation trials. Clinical trial information: NCT07193628 .