IL-13Rα2-specific Allogeneic CAR-T Cells in Recurrent Glioblastoma
Authors: Li Xuetao , Shang Xiaoyun , Liu Jiangang , Zhang Xuewen , Rong Xiaoci , Gan Wenjuan , Zhang Yu , Chen Jie , Wang Lin , Bao Zhen , He Liang , Yan Xigang , Liu Yang , Shao Jie , Xiao Zongyu , Wang Zhimin , Zhang Zhenhua , Wang Biao , Li Bowen , Jiang Yang , Zhu Haiping , Wang Zhong , Wu Yuzhang , Huang Yulun 
Published: June 2023

Abstract
BACKGROUND
Optimal treatment for recurrent glioblastoma is yet to be definitely established. Development of new therapeutic approaches for recurrent glioblastoma are challenging due to multiple factors, including the immunosuppressive tumor microenvironment, the rapid disease progression, the difficulty for large molecules to cross blood brain barrier, the difficulty of collecting/testing tumor tissues. In the past, intra-ventricular infusion of IL-13Rα2-targeted autologous chimeric antigen receptor-T (CAR-T) cells has shown potent anti-tumor activity in one patient with recurrent glioblastoma. However, patients with malignant glioma often suffer from diminished anti-tumor lymphocyte response, with decreased cell count, exhausted function, or even incompetent in vitro expansion. Allogeneic chimeric antigen receptor (CAR) T cell therapy presents an alternative treatment paradigm and brings new hope for these patients.

METHODS
We initiated a prospective exploratory study in which MT026, an IL-13Rα2-specific allogeneic universal CAR-T cell preparations, was administered monthly via intra-lumbar injection in patients with IL-13Rα2-positive recurrent glioblastoma until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow up, or discontinuation for patients’ benefit at investigator’s discretion. The primary end point was occurrence and severity of adverse events. Secondary end points included overall survival, 12-month survival rate, progression-free survival, objective response rate, duration of response, disease control rate and pharmacokinetic parameters.

RESULTS
A total of 5 patients, of whom 4 had Karnofsky Performance Scores (KPS) of <70 and only 1 was 90 and all had wild type IDH1/2 and unmethylated MGMT promoter, received MT026 followed by long-term follow-up till the patients’ death. Among the 5 patients, 1 patient (20%) had a complete response and overall survival of up to 17.5 months, 3 patients (60%) had partial responses, and 1 patient (20%) with stable disease, with an overall objective response rate of 80% and disease control rate of 100%. The mean OS was 10.4 months (95% confidence interval [CI], 4.5 to 16.2). The mean PFS was 5.6 months (95% CI, 3.1 to 8.2). The most common treatment-related abnormal laboratory test and symptom were increased cerebrospinal fluid (CSF) interleukin-6 (5/5, 100%) and fever (4/5, 80%), respectively. No adverse events of grade 3 or greater related to MT026 was reported. All the adverse events recovered or were relieved after treatment. No typical or severe cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome occurred. No graft-versus-host disease was observed. MT026 showed an expansion of approximately 1 day and persistence of over 30 days.

CONCLUSIONS
In patients with recurrent glioblastoma, MT026 resulted in a significantly longer overall survival and a higher objective response rate than history data. MT026 was not associated with any adverse events or toxic effects of grade 3 or higher. (Funded by Chongqing International Institute for Immunology; Chinese Clinical Trial Registry number, ChiCTR2000028801.)