肿瘤细胞治疗研究
英文原题：Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models.
Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models.
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开发了靶向胰腺癌细胞表面表达的间皮素（MSLN）的新型CAR-T 细胞，以克服CAR-T 细胞疗法对胰腺癌患者临床疗效的局限。基于多种含scFv的CAR表达T细胞的结合活性和功能有效性，筛选出与MSLN结合的最佳单链可变片段（scFv）。工程化MSLN CAR-T 细胞表现出对MSLN表达水平特异性的成功抗肿瘤活性。
此外，在携带胰腺癌细胞MIA Paca-2、MSLN过表达MIA Paca-2或内源性表达MSLN的AsPC-1的原位小鼠模型中评估了MSLN CAR-T 细胞的抗癌疗效。小鼠被随机分为对照组、模拟治疗组、MS501 BBz治疗组、MS501 28z治疗组或MS501 28BBz治疗组。通过每周IVIS成像监测小鼠，并收获肿瘤并通过免疫组织化学分析进行分析。MSLN CAR-T 细胞在原位动物模型中产生了治疗效果，在相当数量的小鼠中实现了完全缓解。组织病理学分析表明，CD4+和CD8+ MSLN CAR-T 细胞浸润胰腺肿瘤组织并导致癌细胞清除。
我们的结果证明了MSLN CAR-T 细胞疗法对胰腺癌的抗肿瘤疗效，提示其治疗潜力。
Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level.
Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group.
Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication.
Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential.
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