Peptide-based CAR-NK cells: A novel strategy for the treatment of solid tumors

IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Qianqian Wang , Xin Yuan , Cuijuan Liu , Ying Huang , Lin Li , Yimin Zhu
{"title":"Peptide-based CAR-NK cells: A novel strategy for the treatment of solid tumors","authors":"Qianqian Wang ,&nbsp;Xin Yuan ,&nbsp;Cuijuan Liu ,&nbsp;Ying Huang ,&nbsp;Lin Li ,&nbsp;Yimin Zhu","doi":"10.1016/j.bcp.2025.116741","DOIUrl":null,"url":null,"abstract":"<div><div>CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"232 ","pages":"Article 116741"},"PeriodicalIF":5.3000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006295225000036","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor.

Abstract Image

基于肽的CAR-NK细胞:治疗实体瘤的新策略。
CAR-T细胞疗法已被证明对血液系统肿瘤有效,但移植物抗宿主病和细胞因子释放综合征(CRS)在一定程度上限制了其应用。然而,CAR-T治疗实体肿瘤面临挑战,其中肿瘤特异性抗原(tumor-specific antigens, TSA)的缺乏和免疫抑制肿瘤微环境(immunosuppressive tumor microenvironment, TME)是最重要的因素。CAR-NK在某些方面可能是CAR-T的良好替代品,因为它们可以诱导轻度CRS并且不依赖于hla匹配,但CAR-NK在实体瘤中的疗效仍然有限。携带多种肿瘤靶向分子的CAR细胞可以获得更高的实体肿瘤治疗效果。由于分子量大,多价scFv不能在T细胞上有效展示,且scFv对靶标的高亲和力使其容易引起靶外肿瘤(OTOT)毒性。低分子量和亲和力略低于scFvs的多肽可使免疫细胞显示多肽,从而提高杀伤能力,降低OTOT毒性。在我们的研究中,我们设计了基于肽的CAR-NK细胞来解决CAR-T在实体肿瘤中的困境。首先构建含有A1肽的肽基CAR-NK92MI细胞,并鉴定其对A549肿瘤细胞生长的抑制作用。其次,开发具有同时靶向PD-L1、EGFR和VEGFR2肽的三特异性CAR-NK92MI细胞用于联合治疗。三特异性CAR-NK92MI表现出与基于scfv的CAR-NK92MI相当的杀伤活性。此外,基于肽的CAR NK92MI减轻了OTOT毒性。我们的研究表明,基于肽的CAR-NKs可以作为实体肿瘤治疗的有前途的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Biochemical pharmacology
Biochemical pharmacology 医学-药学
CiteScore
10.30
自引率
1.70%
发文量
420
审稿时长
17 days
期刊介绍: Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
文献相关原料
公司名称
产品信息
索莱宝
PBS
索莱宝
inositol
阿拉丁
D-fluorescein potassium
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信