IL-7 and CCR2b Co-Expression-Mediated Enhanced CAR-T Survival and Infiltration in Solid Tumors.

Abstract

Chimeric antigen receptor T (CAR-T) cells are not effective in solid tumor treatment due to reduced invasion and expansion, and short survival time. This study aimed to explore whether interleukin (IL)-7 and CCR2b expression could improve GD2-CAR-T cell survival and infiltration in neuroblastoma and melanoma treatment. IL-7 and CCR2b were inserted into the classical second-generation CAR structure to construct 7×2b CAR. The 7×2b CAR-T cell phenotypes were evaluated by flow cytometry and the chemokine levels by ELISA. The 7×2b CAR-T cell migration and anti-tumor abilities were detected by Transwell assay and animal experiments in vivo. We report that compared with that of CAR-T cells, 7×2b CAR-T cell IL-7 secretion and CCR2b expression did not affect the T cell surface expression of CAR or CAR-T specificity and efficacy against tumor cells. The 7×2b CAR-T cells could induce IFN-γ secretion in GD2-positive tumor cells, killing them as well as conventional CAR-T cells. Moreover, IL-7 and CCR2b co-expression enhanced the 7×2b CAR-T cell survival and migration. Similar to conventional CAR-T, 7×2b CAR-T cells could also inhibit tumor growth and increase IFN-γ, Gzms-B, and IL-2 expression. Finally, unlike in mice injected with CAR-T cells, CD3 expression was the most abundant in the spleen and tumor tissues in mice injected with 7×2b CAR-T cells. Our study demonstrates that IL-7 and CCR2b co-expression in GD2-CAR-T cells exhibit stronger anti-tumor activity than classical second-generation CAR-T cells, shedding light on the potential novel GD2-positive neuroblastoma and melanoma treatment approach.

• Authors: Guangchao Li, Qing Zhang, Zeping Han, Yangmin Zhu, Huijuan Shen, Zhi Liu, Zhao Zhou, Wen Ding, Siqi Han, Jinhua He, Zhao Yin, Jie Zhou, Ruiming Ou, Min Luo, Shuang Liu
• Journal: Frontiers in oncology (Front Oncol) Vol. 11 Pg. 734593 ( 2021) ISSN: 2234-943X [Print] Switzerland
• PMID: 34778046 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Li, Zhang, Han, Zhu, Shen, Liu, Zhou, Ding, Han, He, Yin, Zhou, Ou, Luo and Liu.