Zhao Zuoyi, Cutmore Lauren C, Baleeiro Renato B, Hartlebury Joseph J, Brown Nicholas, Chard-Dunmall Louisa, Lemoine Nicholas, Wang Yaohe, Marshall John F
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
Cancers (Basel). 2025 Apr 30;17(9):1534. doi: 10.3390/cancers17091534.
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.
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.
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.
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.
背景/目的：嵌合抗原受体T细胞（CAR T）疗法作为一种快速发展的免疫肿瘤学治疗方式，在白血病和淋巴瘤的治疗中取得了显著成功。然而，其在实体瘤中的应用仍然有限。面临的挑战包括肿瘤的异质性、局部免疫抑制、归巢和浸润不良、危及生命的毒性以及缺乏精确的具有免疫活性的代表性研究模型。考虑到胰腺导管腺癌（PDAC）具有典型的致密且免疫抑制的肿瘤微环境（TME）以及早期转移的特点，将其用作模型来应对阻碍CAR T细胞治疗实体瘤的挑战，并为晚期疾病拓展免疫治疗选择。
开发了一种新型的靶向整合素αvβ6的小鼠A20口蹄疫病毒2（A20）CAR T细胞（mA20CART），其显示出高效且特异性的靶向细胞毒性。在具有免疫活性的模型中，mA20CART细胞作为原位胰腺癌的单一疗法显示出一定疗效。因此，在体内评估了一种新型三联疗法方案，即将mA20CART细胞与编码IL-21的溶瘤痘苗病毒和一种TGF-β阻断抗体联合使用。
三联疗法提高了总生存期，改善了CAR T细胞疗法的安全性，减轻了转移并增强了T细胞浸润。值得注意的是，mA20CART的效力依赖于IL-2的补充。
本研究提出了一种靶向αvβ6的小鼠CAR T细胞，为开发用于实体瘤的CAR T细胞技术提供了一种新方法，并为胰腺癌提供了一种潜在的辅助治疗方法。
