工程化诱导神经干细胞联合 GD2 特异性 CAR-NK 对高级别神经胶质瘤的治疗作用。

Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK.

机构信息

Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.

Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China.

出版信息

Cell Oncol (Dordr). 2023 Dec;46(6):1747-1762. doi: 10.1007/s13402-023-00842-5. Epub 2023 Jul 7.

DOI:10.1007/s13402-023-00842-5

PMID:37420122

Abstract

PURPOSE

High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.

METHODS

iNSCs cells expressing HSV-TK (iNSCs) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCs and the combinational therapeutics of iNSCs and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.

RESULTS

PBMC-derived iNSCs possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCs/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCs/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.

CONCLUSIONS

PBMC-derived iNSCs showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCs therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.

摘要

目的

高级别脑胶质瘤由于其侵袭性和对常规化疗和放疗的耐药性，治疗极具挑战性。相反，基于干细胞和免疫细胞的遗传和细胞免疫治疗策略正在成为治疗脑胶质瘤（GBM）的有前途的方法。我们旨在开发一种新的联合免疫治疗策略，通过表达单纯疱疹病毒胸苷激酶（HSV-TK）的基因工程 PBMC 来源诱导神经干细胞（iNSCs）和第二代嵌合抗原受体自然杀伤细胞（CAR-NK）联合治疗来提高 GBM 的治疗效果。

方法

iNSCs 细胞表达单纯疱疹病毒胸苷激酶（iNSCs）和 GD2 特异性嵌合抗原受体自然杀伤细胞（GD2NK92）分别由 PBMC 来源的 iNSCs 和 NK92 细胞系产生。通过体外和体内实验评估了 iNSCs 对 GBM 细胞系的抗肿瘤作用和 iNSCs 与 GD2NK92 的联合治疗效果。

结果

PBMC 来源的 iNSCs 具有体外和体内的肿瘤趋向迁移能力，在存在更昔洛韦（GCV）的情况下通过旁观者效应表现出相当大的抗肿瘤活性。iNSCs/GCV 可以减缓 GBM 的进展并延长荷瘤小鼠的中位生存时间。然而，其抗肿瘤作用仅限于单一疗法。因此，研究了 iNSCs/GCV 和 GD2NK92 联合治疗 GBM 的效果。这种方法在体外和异种移植肿瘤小鼠中显示出更显著的抗肿瘤作用。