4-1BBL-Armed Oncolytic Herpes Simplex Virus Exerts Antitumor Effects in Pancreatic Ductal Adenocarcinoma

• Published in: Vaccines (Basel) 2024-11, Vol.12 (12), p.1309
• Main Authors: Gao, Wenrui, Zhao, Zhuoqian, Bi, Ying, Li, Jinghua, Tian, Na, Zhang, Cuizhu, Pan, Shuyuan, Deng, Li, Zhang, Yuntao
• Format: Article
• Language: English
• Subjects: 4-1BBL; Adenocarcinoma; Analysis; Animal models; Antibodies; Antitumor activity; B cells; Cancer; Cancer therapies; Care and treatment; CD137 antigen; Cell activation; Disease resistance; Drug resistance; Health aspects; Herpes simplex; Herpes simplex virus; Herpes viruses; Immunology; Immunosuppressive agents; Low temperature resistance; Lymphocytes T; Oncolysis; oncolytic virus; Pancreatic cancer; PD-1; PD-1 protein; PDAC; Plasmids; Receptors; Survival; T cells; Therapy; Tumor microenvironment; Tumor necrosis factor; Tumors; Viral antibodies; Viruses
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines12121309

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a notably poor response to therapy due to its immunosuppressive tumor microenvironment (TME) and intrinsic drug resistance. The oncolytic virus (OV) represents a promising therapeutic strategy capable of transforming the "cold" immunological profile of PDAC tumors to a "hot" one by reshaping the TME. 4-1BB (CD137), a crucial member of the tumor necrosis factor receptor superfamily, plays a significant role in T-cell activation and function. In this study, we constructed an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL), the ligand for the 4-1BB receptor, and investigated its therapeutic effects in two mouse models of pancreatic cancer, Pan02_HVEM and KPC. We found that oHSV-4-1BBL remarkably inhibited tumor growth and extended the median survival time in both models. To amplify the therapeutic effect, we further combined oHSV-4-1BBL with PD-1 antibody. This combination therapy not only further suppressed tumor growth but also extended the median survival time by an additional 11 days compared to oHSV (armed with GFP as a control) combined with PD-1 antibody treatment, with some mice achieving complete tumor regression. Our findings confirm the potential of combining oncolytic viral therapy with 4-1BB targeting in enhancing the treatment of pancreatic cancer.