CXCR5 guides migration and tumor eradication of anti-EGFR chimeric antigen receptor T cells

• Published in: Molecular therapy. Oncolytics Vol. 22; pp. 507 - 517
• Main Authors: Li, Guangchao, Guo, Jintao, Zheng, Yanfang, Ding, Wen, Han, Zheping, Qin, Lingyu, Mo, Wenjun, Luo, Min
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: CAR-T cells; chemokine; CXCL13; CXCR5; immunotherapy; lung cancer; Original; lung cancer; CXCR5; chemokine; CXCL13; CAR-T cells; immunotherapy
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2021.07.003

The efficacy of chimeric antigen receptor (CAR) T is still not optimal for solid tumors, partly due to the lack of T cell infiltration to the tumor site. One promising strategy is to guide T cells through tumor-specific chemokines, provided that the matching chemokine receptors are expressed on T cells. Previous reports showed that, for non-small cell lung cancer (NSCLC) patients, the tumor sites express high levels of chemokine CXCL13, whereas CXCR5, the only receptor for CXCL13, is mainly expressed on B cells and follicle helper T cells. Therefore, we engineered an epidermal growth factor receptor (EGFR) CAR-T cell to express a second receptor CXCR5, to facilitate migration of CAR-T cells to the CXCL13-expressing NSCLC tumors, and to minimize EGFR-CAR-T possible off-tumor, on-target toxicity. We first confirmed CXCL13 expression in NSCLC patient blood and cancer tissues and the absence of CXCR5 expression in normal CD3 T cells. Next, we demonstrated that EGFR-CXCR5-CAR-T cells have similar killing activity as EGFR-CAR-T with a cytotoxicity assay in vitro. Furthermore, the in vitro Transwell assay and in vivo xenograft tumor mouse model were used to confirm that EGFR-CXCR5-CAR-T exhibits a significant increase in T cell infiltration to CXCL13-expressing tumors and eradicates the CXCL13-expressing tumors more efficiently. [Display omitted] Chemotactic CAR-T cells show superior trafficking toward tumor sites and enhanced cytotoxicity: a proof of concept study of CXCR5-EGFR-CAR-T for the CXCL13+ NSCLC tumor.