IL-13Rα2 humanized scFv-based CAR-T cells exhibit therapeutic activity against glioblastoma

Chang Xu; Yue Bai; Zhijing An; Yi Hu; Can Zhang; Xiaosong Zhong

doi:10.1016/j.omto.2022.01.002

IL-13Rα2 humanized scFv-based CAR-T cells exhibit therapeutic activity against glioblastoma

Mol Ther Oncolytics. 2022 Jan 10:24:443-451. doi: 10.1016/j.omto.2022.01.002. eCollection 2022 Mar 17.

Authors

Chang Xu¹, Yue Bai¹, Zhijing An¹, Yi Hu¹, Can Zhang¹, Xiaosong Zhong¹

Affiliation

¹ The Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, No. 10, Iron Medicine Road, Yang Fang Dian, Haidian District, Beijing, China.

Abstract

Chimeric antigen receptor (CAR)-modified T cells have exhibited impressive anti-tumor effects in both B cell malignancies and some types of solid tumors. However, single-chain variable fragment (scFv) of a murine monoclonal antibody will induce immune responses, limit CAR-T cell persistence, and thus increase the risk of relapse. This study successfully constructed a CAR-targeting interleukin-13 receptor α2 (IL-13Rα2) according to a murine antibody, and then humanized the scFv sequence to generate another CAR. T cells expressing any of these two CARs demonstrated superior tumor inhibitory effects in vitro and in two xenograft mouse models. However, T cells transduced with humanized CAR have an increased expansion and reduced cytokines, including interleukin-6 and interferon-γ. The top expressed genes clustered in leukocyte-mediated cytotoxicity, and T cell migration and immunological synapse formation contributed to the anti-glioblastoma (GBM) activity of the humanized CAR. In conclusion, we successfully generated a humanized third-generation CAR-targeting IL-13Rα2 and confirmed its anti-GBM efficacy, which provide a candidate method for clinical GBM treatment.

Keywords: adoptive T cell therapy; chimeric antigen receptor-modified T cells; cytokine; expansion; glioblastoma; high-throughput sequencing; interleukin-13 receptor α2; real-time cell analysis.