Arming Oncolytic Herpes Simplex Virus with CXCL-11, IL-12, and a Single-chain antibody against PD-1 to Enhance CAR-T Cell Therapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the primary form of pancreatic cancer, has a very poor prognosis and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy presents a potential treatment approach, yet it is often hindered by several factors, including an immunosuppressive microenvironment, limited tumour infiltration, modest anti-tumour activity, and short-term T cell persistence. Here, we engineered an oncolytic herpes simplex virus expressing CXCL-11, IL-12, and a single-chain antibody against PD-1 (named oHSV30) to enhance CAR-T cell infiltration, cytotoxicity, and persistence in the tumour microenvironment, thereby improving its therapeutic efficacy. In both immunocompetent and immunodeficient syngeneic PDAC models, we demonstrated that the combination of CAR-T cells with the intratumoural administration of oHSV30 significantly reduced tumour burden and prolonged the survival of tumour-bearing mice. Overall, our data suggest that oHSV30 can be a promising adjuvant for CAR-T therapy in PDAC.