Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany.
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Viruses. 2021 Sep 24;13(10):1918. doi: 10.3390/v13101918.
The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of colorectal cancer. Replication and cytotoxic assays revealed that PD-H replicated and lysed colorectal carcinoma cell lines in vitro as well as PD-0. Intratumoral injection of PD-H into subcutaneous DLD-1 tumors in nude mice resulted in strong inhibition of tumor growth and significantly prolonged the survival of the animals, but virus-induced systemic infection was observed in one of the six animals. In a syngenic mouse model of subcutaneously growing Colon-26 tumors, intratumoral administration of PD-H led to a significant reduction of tumor growth, the prolongation of animal survival, the prevention of tumor-induced cachexia, and the elevation of CD3 and dendritic cells in the tumor microenvironment. No virus-induced side effects were observed. After intraperitoneal application, PD-H induced weak pancreatitis and myocarditis in immunocompetent mice. By equipping the virus with target sites of miR-375, which is specifically expressed in the pancreas, organ infections were prevented. Moreover, employment of this virus in a syngenic mouse model of CT-26 peritoneal carcinomatosis resulted in a significant reduction in tumor growth and an increase in animal survival. The results demonstrate that the immune status of the host, the route of virus application, and the engineering of the virus with target sites of suitable microRNAs are crucial for the use of PD-H as an oncolytic virus.
柯萨奇病毒 B3 株 PD-0 被提议作为治疗结直肠癌的新型溶瘤病毒。在这里，我们生成了 PD-0 的 cDNA 克隆，并在结直肠癌的异种移植和同基因模型中分析了由此 cDNA 新生成的病毒 PD-H。复制和细胞毒性测定表明，PD-H 在体外复制并裂解结直肠癌细胞系，与 PD-0 一样。将 PD-H 经皮内注射到裸鼠的皮下 DLD-1 肿瘤中，导致肿瘤生长受到强烈抑制，动物存活时间显著延长，但在 6 只动物中的 1 只观察到病毒引起的全身感染。在皮下生长的 Colon-26 肿瘤的同基因小鼠模型中，PD-H 的瘤内给药导致肿瘤生长显著减少，动物存活时间延长，预防了肿瘤引起的恶病质，以及肿瘤微环境中 CD3 和树突状细胞的升高。未观察到病毒引起的副作用。经腹腔应用后，PD-H 在免疫功能正常的小鼠中引起轻微的胰腺炎和心肌炎。通过为病毒配备特异性表达在胰腺中的 miR-375 的靶标位点，可以预防器官感染。此外，在 CT-26 腹膜癌转移的同基因小鼠模型中使用该病毒，可显著减少肿瘤生长并增加动物存活。结果表明，宿主的免疫状态、病毒应用途径以及使用合适的 microRNAs 的靶标位点对 PD-H 作为溶瘤病毒的使用至关重要。
