Oncolytic adenovirus in treating malignant ascites: A phase II trial and longitudinal single-cell study
Yalei Zhang, Ling Qian, Kun Chen, Sijia Gu, Zhiqiang Meng, Jia Wang, Li Ye, Peng Wang
Abstract
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 processes following oncolytic virotherapy.