National Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Clin Cancer Res. 2020 Jan 15;26(2):465-476. doi: 10.1158/1078-0432.CCR-19-1395. Epub 2019 Nov 25.
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.
We created a Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime. iPSCs from healthy cells were induced to pancreatic tumor cells using gene editing via stable provision of and 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.
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.
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.
胰腺癌仍然是最致命的癌症之一，晚期发现使大多数肿瘤对常规治疗产生抗药性。开发癌症预防可能是改善与这种疾病相关死亡率的最现实选择。在这里，我们使用诱导多能干细胞（iPSC）、基因编辑和肿瘤靶向复制溶瘤病毒开发了一种新的个体化预防和治疗性疫苗方案。
我们创建了一种病毒感染、重编程体细胞衍生肿瘤细胞（VIReST）方案。使用基因编辑通过稳定提供 和 肿瘤驱动突变，将健康细胞的 iPSC 诱导为胰腺肿瘤细胞。这些细胞在进行疫苗接种之前先用溶瘤腺病毒（AdV）或痘苗病毒（VV）进行预感染，以提高疫苗的免疫原性，然后在年轻的 KPC 转基因小鼠中按顺序方案进行疫苗接种，这些小鼠基因编程为发展胰腺癌，以预防和延迟疾病的发展。
用溶瘤 AdV 作为原种或 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。用 iPSC 衍生的肿瘤细胞与 KPC 转基因小鼠的胰腺癌细胞在抗原谱上高度相关，这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，导致疾病的出现和进展延迟，显著延长了 KPC 转基因小鼠的存活时间。重要的是，这种方案耐受性良好且无毒。
这些结果为开发个性化预防癌症疫苗提供了概念验证和强大的技术平台，以预防高危人群的胰腺恶性肿瘤。
