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

IF 4.9 2区 医学 Q2 CELL BIOLOGY
Cellular Oncology Pub Date : 2023-12-01 Epub Date: 2023-07-07 DOI:10.1007/s13402-023-00842-5
Weihua Liu, Yu Zhao, Zhongfeng Liu, Guangji Zhang, Huantong Wu, Xin Zheng, Xihe Tang, Zhiguo Chen
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引用次数: 0

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

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

工程诱导神经干细胞联合gd2特异性CAR-NK治疗高级别胶质母细胞瘤的疗效
目的:高级别胶质母细胞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胶质母细胞瘤(GBM)的有希望的治疗方法。我们的目标是开发一种新的联合免疫治疗策略,以提高表达HSV-TK和第二代CAR-NK细胞的基因工程pbmc衍生的诱导神经干细胞(iNSCs)治疗GBM的疗效。方法:用pbmc来源的iNSCs和NK92细胞系分别生成表达HSV-TK (inskstk)和gd2特异性CAR-NK92 (GD2NK92)的iNSCs细胞。通过体外和体内实验,评价了iNSCsTK的抗肿瘤作用以及iNSCsTK与GD2NK92联合治疗GBM细胞的效果。结果:pbmc衍生的iNSCsTK在体外和体内均具有向肿瘤迁移的能力,在更昔洛韦(GCV)存在下通过旁观者效应表现出相当的抗肿瘤活性。iNSCsTK/GCV可减缓荷瘤小鼠GBM的进展并延长中位生存期。然而,抗肿瘤效果仅限于单一治疗。因此,我们研究了inskstk /GCV和GD2NK92联合治疗GBM的疗效。该方法在体外和异种移植瘤小鼠中显示出更显著的抗肿瘤作用。结论:pbmc衍生的iNSCsTK在体外和体内均表现出明显的致瘤性迁移和抗GCV的有效活性。此外,与GD2NK92联合使用,显著提高了iNSCsTK的治疗效果,延长了荷瘤动物模型的中位生存期。
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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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