Phase I Trial Evaluating Locoregionally-delivered IL13Ra2-targeting CAR T Cells in High-Grade Glioma

We report here a phase I trial (NCT02208362) evaluating locoregional delivery of IL13Ra2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were to evaluate safety and feasibility, and secondary objectives were to assess therapy-related cytokine dynamics, CAR T cell persistence and clinical outcomes. Feasibility and safety were established for three routes of locoregional CAR T cell administration [intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV], with IL13Ra2-CAR T cells being well-tolerated with clinically manageable adverse events at all dose levels. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off protocol therapy. Patients with rGBM treated on Arm 5, utilizing dual ICT/ICV delivery and an optimized manufacturing process exhibited the best overall survival of 10.2 months. . Central nervous system (CNS) increases in inflammatory cytokines, including IFN?, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, suggesting an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors. ClinicalTrials.gov Identifier: NCT02208362 Overall design: Single-cell sequencing of cryopreserved samples was carried out using the 10x Chromium platform. Single-cell RNA sequencing (sc-RNAseq) was carried out on excess available CAR T cell product samples from 62 of the 65 treated patients (40 Tcm, 22 Tn/mem). Additionally, expression levels of cell surface proteins of 27 CAR T product samples (14 Tcm, 13 Tn/mem) were quantified using CITEseq.