A novel TanCAR targeting IL13Rα2 and EphA2 for enhanced glioblastoma therapy

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy has been shown to be an effective strategy for combatting non-solid tumors; however, CAR-T therapy is still a challenge for solid tumors, such as glioblastoma. To improve CAR-T therapy for glioblastoma, a new TanCAR, comprising the tandem arrangement of IL13 (4MS) and EphA2 scFv, was generated and validated in vitro and in vivo. In vitro, the novel TanCAR-redirected T cells killed glioblastoma tumor cells by recognizing either IL-13 receptor α2 (IL13Rα2) or EphA2 alone or together upon simultaneous encounter of both targets, but did not kill normal cells bearing only the IL13Rα1/IL4Rα receptor. As further proof of principle, the novel TanCAR was tested in a subcutaneous glioma xenograft mouse model. The results indicated that the novel TanCAR-redirected T cells produced greater glioma tumor regression than single CAR-T cells. Thus, the novel TanCAR-redirected T cells kill gliomas more efficiently and selectively than a single IL13 CAR or EphA2 scFv CAR, with the potential for preventing antigen escape and reduced off-target cytotoxicity.