Oncolytic adenovirus in treating malignant ascites: A phase II trial and longitudinal single-cell study

作者：Yalei Zhang, Ling Qian, Kun Chen, Sijia Gu, Zhiqiang Meng, Jia Wang, Li Ye, Peng Wang · 发表于：Molecular Therapy · 年份：2024 · DOI：10.1016/j.ymthe.2024.04.029 · 被引用次数：32 · 研究领域：Virus-based gene therapy research、Viral Infectious Diseases and Gene Expression in Insects、Cancer Research and Treatments

Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5–73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8 + T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6 + and GZMK + CD8 + T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A + dendritic cells and GZMK + CD8 + T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular process...