A Virus-Infected, Reprogrammed Somatic Cell-Derived Tumor Cell (VIReST) Vaccination Regime Can Prevent Initiation and Progression of Pancreatic Cancer
A Virus-Infected, Reprogrammed Somatic Cell-Derived Tumor Cell (VIReST) Vaccination Regime Can Prevent Initiation and Progression of Pancreatic Cancer
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病毒感染、重编程体细胞衍生肿瘤细胞 (VIReST) 疫苗接种方案可以预防胰腺癌的发生和进展
DOI：
10.1158/1078-0432.ccr-19-1395
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发表时间：
2020-01-15
影响因子：
11.5
通讯作者：
Wang, Yaohe
中科院分区：
文献类型：
--
作者：
Lu, Shuangshuang;Zhang, Zhe;Wang, Yaohe
目的：胰腺癌仍然是最致命的癌症之一，晚期检测使得大多数肿瘤对传统疗法难以治疗。发展癌症预防可能是提高与这种疾病相关的死亡率的最现实的选择。在这里，我们利用诱导多能干细胞（iPSC）、基因编辑和肿瘤靶向复制溶瘤病毒开发了一种新型个体化预防和治疗性疫苗接种方案。实验设计：我们创建了一种病毒感染的、重编程的体细胞来源的肿瘤细胞（VIReST）方案。通过稳定提供 KRas(G12D) 和 p53(R172H) 肿瘤驱动突变，使用原位基因编辑将来自健康细胞的 iPSC 诱导为胰腺肿瘤细胞。这些细胞用溶瘤腺病毒（AdV）作为初免或痘苗病毒（VV）作为加强免疫进行预感染，以提高疫苗的免疫原性，然后将疫苗按序贯方案递送给年轻的KPC转基因小鼠，经过基因编程以发展为胰腺癌，以预防和延缓疾病发展。 结果：用溶瘤腺病毒（AdV）作为初免或VV作为加强免疫预感染的肿瘤细胞是诱导肿瘤特异性免疫的最佳方案，iPSC衍生的肿瘤细胞是抗原库与 KPC 转基因小鼠的胰腺癌细胞高度相关，表明个体的干细胞可以提供抗原匹配的全肿瘤细胞疫苗。 VIReST 疫苗接种引发了肿瘤特异性 T 细胞反应，从而延迟了疾病的出现和进展，并显着延长了 KPC 转基因小鼠的生存期。重要的是，该方案耐受性良好且无毒。结论：这些结果为开发个性化预防性癌症疫苗以预防高危个体的胰腺恶性肿瘤提供了概念证明和强大的技术平台。
Purpose: Pancreatic cancer remains one of the most lethal cancers, and late detection renders most tumors refractory to conventional therapies. Development of cancer prophylaxis may be the most realistic option for improving mortality associated with this disease, Here, we develop a novel individualized prophylactic and therapeutic vaccination regimen using induced pluripotent stem cells (iPSC), gene editing, and tumor-targeted replicating oncolytic viruses.Experimental Design: We created a Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime. iPSCs from healthy cells were induced to pancreatic tumor cells using in situ gene editing via stable provision of KRas(G12D) and p53(R172H) tumor driver mutations. These cells were preinfected with oncolytic Adenovirus (AdV) as prime or Vaccinia virus (VV) as boost, to improve vaccine immunogenicity, prior to delivery of vaccines in a sequential regime to young KPC transgenic mice, genetically programmed to develop pancreatic cancer, to prevent and delay disease development.Results: Tumor cells preinfected with oncolytic AdV as prime or VV as boost were the best regime to induce tumor-specific immunity, iPSC-derived tumor cells were highly related in antigen repertoire to pancreatic cancer cells of KPC transgenic mice, suggesting that an individual's stem cells can provide an antigenically matched whole tumor cell vaccine. The VIReST vaccination primed tumor-specific T-cell responses, resulting in delayed disease emergence and progression and significantly prolonged survival of KPC transgenic mice. Importantly, this regime was well-tolerated and nontoxic.Conclusions: These results provide both proof of concept and a robust technology platform for the development of personalized prophylactic cancer vaccines to prevent pancreatic malignancies in at-risk individuals.