工程化间充质干细胞抗肿瘤研究进展<sup>*</sup>

doi:10.13523/j.cb.2304001

中国生物工程杂志

2023, Vol. 43

Issue (11): 56-65 DOI: 10.13523/j.cb.2304001

综述

工程化间充质干细胞抗肿瘤研究进展^*

王沁尧^1,²,王溪溪^1,²,李丽²,胡耀晟²,撒亚莲^2,^**(

)

1 昆明理工大学医学院昆明 650500
2 云南省第一人民医院(昆明理工大学附属医院)临床医学研究中心(云南省临床病毒学重点实验室) 昆明 650032

Advances in Engineered Mesenchymal Stem Cells in Tumor Therapy

WANG Qin-yao^1,²,WANG Xi-xi^1,²,LI Li²,HU Yao-sheng²,SA Ya-lian^2,^**(

)

1 Medical School, Kunming University of Science and Technology, Kunming 650500, China
2 Center for Clinical Medicine Research(Yunnan Provincial Key Laboratory of Clinical Virology), The First People’s Hospital of Yunnan Province (Affiliated Hospital of Kunming University of Science and Technology), Kunming 650032, China

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摘要：

间充质干细胞(mesenchymal stem cells, MSCs)是一类来源广泛的成体多能干细胞,因其具有低免疫原性、易向受损组织归巢、有旁分泌效应与免疫调节能力以及易于工程化操作等特点,在肿瘤治疗中具有一定优势。尽管目前在肿瘤治疗中应用MSCs存在争议,但已观察到过表达抗肿瘤基因(自杀基因、肿瘤坏死因子、白介素和干扰素等)或荷载溶瘤病毒、纳米颗粒、抗癌药物等经工程化改造和修饰的MSCs及其胞外囊泡能主动归巢到肿瘤组织,发挥抗肿瘤作用。目前已有工程化MSCs应用于复发性多形性胶质母细胞瘤的临床研究。因而概述MSCs特性以及工程化MSCs靶向肿瘤细胞和/或微环境的治疗研究,以期为MSCs临床转化及肿瘤治疗拓展新视野。

关键词： 间充质干细胞; 肿瘤治疗; 工程化修饰; 胞外囊泡

Abstract:

Mesenchymal stem cells (MSCs) are adult multipotent stem cells possessing the advantages of rich and wide sources, low immunogenicity, homing to the tissue of injury, paracrine activity, immunomodulation capacity, and easiness to be engineered. With the above-mentioned advantages, MSCs may have great application value in the treatment of cancer. Despite the controversial roles of MSC in cancer therapy, engineering MSCs with homing capacity to tumor tissues show great antitumor potential for delivering anticancer agents, suicide genes, and oncolytic viruses to tumors. Current clinical trial utilizing engineered MSCs in GBM treatment was shown to exert anti-GBM activity. Therefore, the following review elaborates on the characteristics of MSCs as well as the effects of engineering MSCs on tumor cells and their microenvironments, in order to provide new insights into MSCs’ value in translational medicine and tumor treatment.

Key words: Mesenchymal stem cells (MSCs) Tumor treatment Engineered modification Extracellular vesicle

收稿日期: 2023-04-04 出版日期: 2023-12-01

ZTFLH:

Q26

基金资助: *国家自然科学基金(82060028);云南省临床病毒学重点实验室项目(202205AG070053);云南省卫生科技计划(L-2019003)

通讯作者: **撒亚莲 E-mail: sayalian@126.com

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引用本文:

王沁尧, 王溪溪, 李丽, 胡耀晟, 撒亚莲. 工程化间充质干细胞抗肿瘤研究进展^*[J]. 中国生物工程杂志, 2023, 43(11): 56-65.

WANG Qin-yao, WANG Xi-xi, LI Li, HU Yao-sheng, SA Ya-lian. Advances in Engineered Mesenchymal Stem Cells in Tumor Therapy. China Biotechnology, 2023, 43(11): 56-65.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2304001 或 https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I11/56

细胞来源		疾病类型		移植方式	病例数		安全性和有效性			注册编号/文献
脐带MSCs		急性GVHD		外周血干细胞移植前4~6 h静脉输注(1×10⁶/kg)	50		无输注细胞相关不良反应单剂量MSCs能促进造血干细胞植入,减少急性GVHD的发病率,疾病复发率下降			ChiCTR-INR- 16008399^[20]
同种异体骨髓MSCs		激素难治性慢性GVHD		6~12月内反复静脉输注(2×10⁶/kg)	11		无输注细胞相关不良反应 6名患者疾病进程和生活质量得到改善;CXCL9和CXCL10可作为MSCs治疗的早期生物标志物			NCT01522716^[21]
脐带MSCs	激素难治性急性GVHD		静脉注射低剂量(2×10⁶/kg)或高剂量(10×10⁶/kg)			10		半年内无输注细胞相关不良反应低剂量组和高剂量组输注耐受性良好,未观察到异位组织形成,70%患者的临床症状得到明显改善	NCT03158896^[22]
同种异体骨髓MSCs	急性GVHD		脐带血移植前4 h经骨髓腔内注射(≥0.2×10⁶/kg)5 mL			5		一年内无输注细胞相关不良反应 MSCs能促进脐带血移植植活率,且1年内未见疾病复发	UMIN000024291^[23]
同种异体骨髓来源MSCs	激素难治性急性GVHD		在使用二线药物的7天内,静脉注射(1×10⁶/kg),每周一次,连续4周为一个周期			203		2年内未观察到输注细胞相关不良反应 MSCs联合巴利西单抗和钙调磷酸酶抑制剂可以增加激素耐药急性GVHD的疗效,减少抗排异药物毒性和GVHD复发风险,并且患者的耐受性良好	NCT02241018^[24]
自体骨髓MSCs	难治性急性或慢性GVHD		静脉输注(2×10⁶/kg),按照输注次数分为三组(单剂量、每周2次、每周4次)			11		3个月内未观察到输注细胞相关不良反应,未观察到剂量限制性毒性难治性急性GVHD组的病人缓解率较高	NCT02359929^[25]
脐带MSCs	激素耐药性急性GVHD		静脉输注(1×10⁶/kg或2×10⁶/kg)			7		16周内未观察到输注细胞相关不良反应显著抑制CD4⁺和CD8⁺T细胞增殖,NK细胞数明显增加,而IL-12、IL-17和IL-33水平下降,CCL2和CCL11水平增加	UMIN000032819^[26]
同种异体骨髓MSCs	急性GVHD		静脉输注(1×10⁶/kg)			43		30天内未观察到输注细胞相关不良反应输注MSCs对异体造血干细胞移植后患者T细胞亚群的恢复有积极作用	NCT01941394^[27]

表1 MSCs治疗异基因造血干细胞移植后GVHD的临床研究

表2 未修饰MSCs在肿瘤治疗中的两面性

表3 工程化MSCs细胞外囊泡携载非编码RNA用于肿瘤治疗

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