A phase 1 study of B7H3 CAR-T cells administered intracranially in recurrent glioblastoma.

2018 Background: Glioblastoma (GBM) is an aggressive malignancy with median survival of approximately 2 years from initial diagnosis and 9 months after first progression. Effective treatments in the recurrent setting following upfront chemoradiation and adjuvant temozolomide are limited. The transmembrane glycoprotein B7H3 is over-expressed in GBM and chimeric antigen receptor T cells targeting B7H3 (B7H3-CART) have shown activity in several preclinical cancer models. Intracranial delivery of B7H3-CART may optimize targeting the immune response to the tumor microenvironment while limiting systemic toxicity. Methods: We conducted a single-arm phase 1 study in patients with recurrent GBM undergoing repeat resection. B7H3-CART was administered via intratumoral and intraventricular Ommaya reservoirs monthly for a planned 6 months or until confirmed disease progression. When possible per investigator discretion, the dose was divided evenly between the two reservoirs. The primary endpoints were safety and manufacturing feasibility, with secondary endpoints focused on preliminary efficacy. Dose escalation was planned according to a standard 3+3 design (dose level 1: 10x10 6 cells; level 4 (max): 100x10 6 ). Adverse events within 28 days of first dose and at least possibly related to B7H3-CART were considered dose-limiting toxicities (DLTs) if meeting additional criteria: any grade 5 toxicity, grade 4 cytokine release syndrome, neutropenia, or thrombocytopenia lasting > 14 days, or any non-hematologic grade 3 toxicity lasting > 72 hours. Neurotoxicity was considered a DLT if grade 4 for > 96 hours or new-onset grade 3 for > 28 days. Serial CSF and serum samples were collected for translational studies to determine immune cell kinetics and the mechanisms of activity and resistance. Results: Eleven patients were enrolled, underwent apheresis, and had B7H3-CART successfully manufactured. Nine received at least one dose of B7H3-CART and were evaluable in the dose escalation cohort. One patient in dose level 2 (25x10 6 cells) experienced a DLT (grade 3 hypertension). No additional DLTs were observed in this dose level after expansion to 6 patients, and the recommended phase 2 dose was established at 25x10 6 cells. Toxicity otherwise has been primarily related to tumor inflammation-associated neurotoxicity (TIAN), observed after 29 of 36 infusions (81%), and managed acutely with anakinra and dexamethasone. The median overall survival (mOS) from date of enrollment for patients receiving at least one dose of B7H3-CART is 14.6 months (95% CI: 2.3 - 26.8 months). One patient is currently receiving B7H3-CART and 4 others are being clinically followed up to 22 months from enrollment. Conclusions: Intracranial administration of B7H3-CART in recurrent GBM is technically feasible and safe. TIAN was common but manageable and reversible with immunomodulators. Correlative analyses on surgical tissue, CSF, and serum are ongoing. Clinical trial information: NCT05474378 .