Safety and tolerability of intraventricular CARv3-TEAM-E T cells following lymphodepleting chemotherapy in recurrent glioblastoma: INCIPIENT trial.

2017 Background: CAR T therapy is a novel, promising approach in glioblastoma (GBM) but tumor heterogeneity can limit efficacy when a single antigen is targeted. We designed a second-generation CAR T molecule that targets epidermal growth factor receptor vIII (EGFRvIII) and also secretes a T-cell–engaging antibody molecule (TEAM) against wild-type EGFR. Methods: In a phase 1, first-in-human study (INCIPIENT, NCT05660369), patients with recurrent GBM with EGFRvIII mutation and/or EGFR amplification were eligible to receive up to 6 intraventricular doses of 10x106 CAR T cells via Ommaya catheter after lymphodepleting chemotherapy (LDC) with fludarabine and cyclophosphamide. Primary objective was safety and tolerability and secondary objective was preliminary tumor response determined by iRANO criteria. Results: CAR T manufacturing was successful for all patients. Seven patients (5 male) received at least 1 intraventricular infusion. Two patients received 2 infusions (1 for progressive disease (PD) and 1 without PD). One patient received 3 infusions after experiencing initial PD. No DLTs occurred. All patients experienced cytokine release syndrome (CRS) grade 1 lasting 0-9 days with only 1 patient experiencing CRS grade 2 for 1 day. One patient experienced ICANS grade 1 that lasted 2 days. All patients experienced tumor inflammation-associated neurotoxicity grade 1 with a duration of 2-9 days. Adverse events (grade 3-4) at least possibly related to CAR T were febrile neutropenia (N = 1) and neutrophil count decrease (N = 1). Toxicity was managed with supportive care without need for ICU monitoring and 3 patients received at least 1 dose of anakinra (max duration = 4 days, median = 1 day). Best response was stable disease (SD) in 5 patients with 1 patient achieving SD for 6 months after a single infusion and another experiencing a 33% decrease in tumor diameter after 2 infusions. All patients are alive 3-8 months after first infusion. From the preceding safety run-in arm of the study (without LDC), one patient survived 12 months and another is still alive > 20 months after infusion. Conclusions: Intraventricular CARv3-TEAM-E infusions were well tolerated, even with multiple doses, and no DLTs were noted. Toxicity was manageable in all patients with supportive care and anakinra was administered to 3 patients. Steroids were not required to manage toxicity. A subset of patients experienced SD for several months. Clinical trial information: NCT05660369 .