65 patients with high-grade, recurrent glioma received anti-IL-13Rα2 CAR T cells at different doses (2-200e6 cells) and injection sites (intratumoral, intraventricular, or combined). For CAR T manufacturing, patient PBMCs were sorted either as CD62L+CD45RA- (central memory, CM) or CD62L+ alone (naive/stem-like/CM); the latter had superior memory and functionality. Treatment was safe, and 29/58 patients achieved stable disease, leading to one complete and two partial responses. CAR T cells were detected in CSF, tumor cavity, and blood, with persistence ≥7 days in CSF. High IFNγ among CSF-induced cytokines, combined delivery route, and pre-treatment tumor CD3+ score associated with improved survival.
Contributed by Alex Najibi
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 .
Author Info: (1) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, C
Author Info: (1) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. cbrown@coh.org. (2) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (3) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (4) Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (5) The Translational Genomics Research Institute, Phoenix, AZ, USA. (6) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. Bone Marrow Transplantation Center, the First Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China. (7) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (8) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (9) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (10) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (11) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (12) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (13) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (14) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (15) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (16) Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (17) Department of Diagnostic Radiology, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (18) Department of Diagnostic Radiology, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (19) Department of Clinical Research, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (20) Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (21) Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (22) Departments of Immuno-Oncology and Pediatrics, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (23) Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (24) Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (25) Department of Medical Oncology, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (26) Department of Stem Cell Biology & Regenerative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (27) Department of Pathology, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (28) The Translational Genomics Research Institute, Phoenix, AZ, USA. (29) Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA. (30) Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, USA.
