Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362.

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“…Fifty percent stable disease and two complete responses were induced by the CAR-T cell treatment MB-101 (Mustang Bio) in 65 heavily pretreated patients with recurrent and refractory, high-grade malignant glioma enrolled in a dose-escalation Phase 1 trial. 1 The regimen, which was tested with two routes of administration (intratumoral and intraventricular) and their combination, was well tolerated with no dose-limiting toxicities.…”

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“…As the efficient homing of CAR-T-cells into the brain determines the efficacy of antitumor immunity, novel approaches to enhance the presence of CAR-T-cells are urgently needed. Locoregional delivery modalities, such as intraventricular (ICV), intracavitary (IC), or intratumor (IT) immunotherapy applications, have been successfully investigated in multiple human phase I GBM trials as an alternative to surmounting inherent biological barriers [15,18,22,50]. These targeted delivery routes hold the potential to achieve lower drug concentrations, thereby mitigating the risk of off-target toxicities.…”

“…These targeted delivery routes hold the potential to achieve lower drug concentrations, thereby mitigating the risk of off-target toxicities. However, recent clinical trials have reported the presence of ICV/IT-administered CAR-T-cells in the periphery, and further investigations are needed to determine if local delivery can truly prevent off-target toxicities [22]. Furthermore, all techniques require invasive surgery.…”

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“…Nonetheless, finding the right combination of therapies and methods to activate the immune system such as through the use of adoptive cell therapies or therapeutic vaccines continues to hold promise in the search for effective treatments against this aggressive brain tumor [ 140 ]. For example, a phase 1 trial evaluating a locoregional delivery of IL-13Rα2-targeting chimeric antigen receptor (CAR)-T cells in recurrent high-grade glioblastomas showed promising clinical activity [ 141 ]. Similarly, intrathecal bivalent CAR-T cells targeting EGFR and IL13Rα2 in recurrent glioblastomas reported interim results showing manageable toxicity and encouraging progression-free survival [ 142 ].…”