文章：

溶瘤病毒与TGF-β抗体阻断联合应用增强αvβ6靶向CAR T细胞在免疫健全模型中治疗胰腺癌的疗效

The Combination of Oncolytic Virus and Antibody Blockade of TGF-β Enhances the Efficacy of αvβ6-Targeting CAR T Cells Against Pancreatic Cancer in an Immunocompetent Model

原文发布日期：30 April 2025

DOI: 10.3390/cancers17091534

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer.

摘要翻译： 

背景/目的：嵌合抗原受体T细胞疗法作为一种快速发展的免疫肿瘤学治疗手段，在白血病和淋巴瘤治疗中已取得显著成功，但其在实体瘤中的应用仍受限。面临的挑战包括肿瘤异质性、局部免疫抑制、归巢与浸润能力不足、危及生命的毒性反应以及缺乏精准有效的免疫活性研究模型。鉴于胰腺导管腺癌通常具有致密且具免疫抑制性的肿瘤微环境及早期转移特性，本研究以其为模型，旨在解决阻碍CAR T细胞疗法应用于实体瘤的难题，并为晚期疾病拓展免疫治疗选择。方法：本研究开发了一种靶向整合素αvβ6的新型鼠源A20FMDV2 CAR T细胞，该细胞展现出高效且特异性的靶向杀伤能力。在免疫活性模型中，该细胞作为原位胰腺癌单药疗法显示出有限疗效。因此，研究在体内评估了由该CAR T细胞、编码IL-21的溶瘤痘苗病毒及TGF-β阻断抗体组成的新型三联疗法方案。结果：三联疗法显著提高总体生存率，改善CAR T细胞治疗安全性，抑制转移并增强T细胞浸润。值得注意的是，该CAR T细胞的效力依赖于IL-2的补充。结论：本研究提出的靶向αvβ6鼠源CAR T细胞，为实体瘤CAR T技术开发提供了新思路，并为胰腺癌治疗提供了潜在的辅助治疗方案。

原文链接：

The Combination of Oncolytic Virus and Antibody Blockade of TGF-β Enhances the Efficacy of αvβ6-Targeting CAR T Cells Against Pancreatic Cancer in an Immunocompetent Model