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Customized Viral Immunotherapy for HPV-Associated Cancer

机译:针对HPV相关癌症的定制病毒免疫疗法

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The viral-transforming proteins E6 and E7 make human papillomavirusa??positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 ?? 106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1 clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer, as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847a??59. ??2017 AACR .
机译:病毒转化蛋白E6和E7使人乳头瘤病毒阳性(HPV +)恶性肿瘤成为癌症免疫治疗的诱人靶标。但是,治疗性疫苗接种在晚期疾病的治疗中发挥有限的功效。我们设计了一种策略,可基于来自HPV血清型16和18的减毒转基因,并入MG1-Maraba病毒疗法(MG1-E6E7),诱导针对E6和E7蛋白质多个表位的实质性特异性免疫反应。引入转基因的突变分别消除了E6和E7干扰p53和成视网膜细胞瘤的能力,同时保持了调用肿瘤特异性多功能CD8 + T细胞反应的能力。与仅使用初免疫苗处理的小鼠相比,用MG1-E6E7进行的增强显着增加了T细胞反应的强度(观察到每只小鼠大于50 ?? 106 E7特异性CD8 + T细胞,代表增强的平均39倍)动物)。 HPV +鼠模型TC1中的MG1-E6E7疫苗以CD8 ​​+依赖性方式清除大肿瘤,并产生持久的免疫记忆。 MG1-Maraba可以在体内急性改变肿瘤微环境,并利用HPV +癌症的分子标志,如HPV +患者肿瘤活检标本的明显感染所证明的,因此,MG1-Maraba理想地适合作为针对临床HPV +癌症的溶瘤治疗。这种方法有可能直接转化为人类临床肿瘤学,以解决各种导致全球范围内高发病率和高死亡率的HPV相关肿瘤。癌症免疫研究; 5(10); 847a ?? 59。 2017年AACR。

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