Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
Int Immunopharmacol. 2024 Mar 10;129:111631. doi: 10.1016/j.intimp.2024.111631. Epub 2024 Feb 14.
The treatment of breast cancer (BC) remains a formidable challenge due to the emergence of drug resistance, necessitating the exploration of innovative strategies. Chimeric antigen receptor (CAR)-T cell therapy, a groundbreaking approach in hematologic malignancies, is actively under investigation for its potential application in solid tumors, including BC. Trophoblast cell surface antigen 2 (Trop2) has emerged as a promising immunotherapeutic target in various cancers and is notably overexpressed in BC. To enhance therapeutic efficacy in BC, a fourth-generation CAR (CAR4) construct was developed. This CAR4 design incorporates an anti-Trop2 single-chain variable fragment (scFv) fused with three costimulatory domains -CD28/4-1BB/CD27, and CD3ζ. Comparative analysis with the conventional second-generation CAR (CAR2; 28ζ) revealed that anti-Trop2 CAR4 T cells exhibited heightened cytotoxicity and interferon-gamma (IFN-γ) production against Trop2-expressing MCF-7 cells. Notably, anti-Trop2 CAR4-T cells demonstrated superior long-term cytotoxic functionality and proliferative capacity. Crucially, anti-Trop2 CAR4-T cells displayed specific cytotoxicity against Trop2-positive BC cells (MDA-MB-231, HCC70, and MCF-7) in both two-dimensional (2D) and three-dimensional (3D) culture systems. Following antigen-specific killing, these cells markedly secreted interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), IFN-γ, and Granzyme B compared to non-transduced T cells. This study highlights the therapeutic potential of anti-Trop2 CAR4-T cells in adoptive T cell therapy for BC, offering significant promise for the advancement of BC treatment strategies.
乳腺癌（BC）的治疗仍然是一个艰巨的挑战，因为出现了耐药性，需要探索创新的策略。嵌合抗原受体（CAR）-T 细胞疗法在血液恶性肿瘤中是一种开创性的方法，目前正在积极研究其在实体瘤中的潜在应用，包括 BC。滋养细胞表面抗原 2（Trop2）在各种癌症中已成为一种有前途的免疫治疗靶点，在 BC 中明显过表达。为了提高 BC 的治疗效果，开发了第四代 CAR（CAR4）构建体。这种 CAR4 设计将抗 Trop2 单链可变片段（scFv）与三个共刺激结构域 -CD28/4-1BB/CD27 和 CD3ζ 融合。与传统的第二代 CAR（CAR2；28ζ）进行比较分析表明，抗 Trop2 CAR4 T 细胞对表达 Trop2 的 MCF-7 细胞表现出更高的细胞毒性和干扰素-γ（IFN-γ）产生。值得注意的是，抗 Trop2 CAR4-T 细胞表现出优越的长期细胞毒性功能和增殖能力。至关重要的是，抗 Trop2 CAR4-T 细胞在二维（2D）和三维（3D）培养系统中对 Trop2 阳性 BC 细胞（MDA-MB-231、HCC70 和 MCF-7）表现出特异性细胞毒性。在抗原特异性杀伤后，与非转导 T 细胞相比，这些细胞明显分泌白细胞介素-2（IL-2）、肿瘤坏死因子-α（TNF-α）、IFN-γ 和 Granzyme B。这项研究强调了抗 Trop2 CAR4-T 细胞在 BC 过继性 T 细胞治疗中的治疗潜力，为 BC 治疗策略的进步提供了重要的希望。
