Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Abstract

Chimeric antigen receptor (CAR) T cell therapy is at early stages of clinical testing for solid tumors. We report here a completed phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM; 2 + recurrences). Primary endpoints were safety and feasibility, with secondary endpoints measuring therapy-related bioactivity. Weekly intratumoral (ICT) and/or intraventricular (ICV) administration of IL13Rα2-CAR T cells was well-tolerated with clinically manageable adverse events. 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 with dual ICT/ICV delivery and an optimized manufacturing process exhibited superior overall median survival of 10.2 months, compared to 6.1 months for other treatment arms. Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, 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, indicating 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.

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R⍺2-targeting CAR T cells: an interim analysis

“…Consistent with other studies, including our extensive experience with adult glioblastoma patients receiving IL13BBζ-CAR T cells 10,14 , and consistent with patients' metronomic clinical symptoms, intraventricular delivery of CAR T cells was associated with post-infusion increases in CSF in ammatory cytokines such as IFNγ, IL-6, IL-8, CCL4, and CXCL10 (Figure S12). These spikes were detected the day after each infusion and dissipated before the next CAR T infusion.…”

“…These spikes were detected the day after each infusion and dissipated before the next CAR T infusion. Moreover, studies with IL13BBζ-CAR T cells in adult glioblastoma nds that levels of interferon pathway cytokines IFNγ, CXCL9, and CXCL10 are positively associated with clinical response 14 . Peripheral blood serum cytokine levels, in contrast, were much more stable both within and between cycles; this is also similar to what has been reported by other groups 5,7,14,15 .…”

“…Given the demonstrated safety of IL13Rα2-targeting CAR T cells in adults with brain tumors 14 , the documented superiority of locoregional delivery of these cells 15,23 , and the ample evidence indicating that lymphodepletion improves e cacy of locoregionally-delivered solid tumor-targeted CAR T cells 5,24 , our trial design incorporates lymphodepletion before intraventricular IL13BBζ-CAR T cell therapy for pediatric patients with documented IL13Rα2 + recurrent or refractory brain tumors.…”

“…mutated cytokine rather than a single-chain variable fragment 15,20 . This CAR incorporates an IgG4-based hinge and linker, a CD4-derived transmembrane domain, and a 4-1BB-derived costimulatory domain, and has been extensively investigated in preclinical and adult clinical studies 9,10,[14][15][16] . Our group has shown that CAR T cells are more effective when manufactured from less mature initial T cell populations 21,22 .…”

“…Furthermore, preclinical 16,17 and early clinical evidence indicates that systemic lymphodepletion improves the e cacy of locoregionally-delivered CAR T cells 5,24 . Importantly, IL13BBζ-CAR T cells are capable of mediating a remarkable clinical response in adult glioblastoma patients 10 , and show encouraging evidence of clinical activity in a large cohort of heavily-pretreated adult glioblastoma patients 14 .…”