为肝细胞癌武装 GPC3 CAR T 细胞：多少才足够，下一步是什么？
Armouring GPC3 CAR T cells for hepatocellular carcinoma: how much is enough and what comes next?
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
联合免疫治疗策略在多灶性肝细胞癌模型中的协同效应
英文原题：Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma.
研究概要
免疫检查点抑制剂联合治疗是晚期肝细胞癌（HCC）患者的最佳治疗选择，但需要提高疗效以改善缓解率。
中文摘要
免疫检查点抑制剂联合治疗是晚期肝细胞癌（HCC）患者的最佳治疗选择，但仍需提高疗效以改善应答率。我们通过水动力基因转移技术在小鼠肝细胞中导入c-myc，并利用CRISPR-Cas9介导的p53基因破坏，构建了多灶性HCC模型以测试免疫疗法。此外，诱导荧光素酶、EGFP和黑素体抗原gp100的共表达有助于研究其潜在免疫学机制。我们发现，使用抗CTLA-4 + 抗PD1单克隆抗体联合治疗小鼠可实现肿瘤部分消退并改善生存期。然而，在此基础上加入重组IL-2或抗CD137单克隆抗体可显著改善这两种结局。将肿瘤特异性过继T细胞疗法与aCTLA-4/aPD1/rIL2或aCTLA-4/aPD1/aCD137方案联合，可以协同方式增强疗效。多重组织免疫荧光和活体显微镜检查显示，联合免疫治疗可增强T细胞浸润及T淋巴细胞在肿瘤内的功能。
展开英文摘要原文
Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.
论文信息
- 作者
- Ochoa MC、Sanchez-Gregorio S、de Andrea CE、Garasa S、Alvarez M、Olivera I、Glez-Vaz J、Luri-Rey C
- 第一作者单位
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.Spain
- 通讯作者单位
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: mochnie@unav.es.Spain
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports. Medicine2023 Apr 18
- 原文标识
- PubMed 37040772 · DOI 10.1016/j.xcrm.2023.101009