A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI:10.1038/s44321-024-00184-1
Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li
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Abstract

The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.

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新抗原特异性TCR-T细胞治疗HLA-A*2402阳性实体瘤的治疗方案
新抗原特异性 TCR-T 细胞的采纳性转移对肿瘤细胞具有强大的细胞毒性,在各种临床前人类癌症中显示出良好的疗效。在这项研究中,我们首次发现了一种功能性 TCR Tcr-1,它能选择性识别大多数滑膜肉瘤共有的 SYT-SSX 融合新抗原。表达 Tcr-1 的工程 T 细胞(Tcr-T1)在体外和体内对滑膜肉瘤细胞均表现出 HLA-A*2402 限制性抗原特异性抗肿瘤功效。此外,为了扩大其应用范围,我们开发了一种合作治疗模式,即将外源性 SYT-SSX 融合新抗原载入由 mPEG-PVGLIG-PCL 共聚物形成的刺激响应型纳米颗粒(NPs)(Neo-AgNPs)中,用于肿瘤靶向递送。正如预期的那样,Neo-AgNPs 被证明具有很强的肿瘤穿透性和局部释放性。尽管其他 HLA-A*2402 阳性的恶性肿瘤细胞系存在固有的突变特征,但这种改性仍能引导工程化 Tcr-T1 对抗这些细胞系,并具有显著的抗原特异性细胞毒性。有了这些有利的数据,我们建立的合作治疗模式具有进一步临床研究的巨大潜力,并为未来的 TCR-T 细胞疗法开发提供了新的见解。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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