Harnessing Th1 Immunity with a Dual-Armed Oncolytic Virus for Pancreatic Cancer Therapy

The study investigates an oncolytic virus, LOAd703, designed to stimulate the immune system against pancreatic cancer. This virus is engineered to carry two immunostimulatory molecules, CD40L and 4-1BBL, to enhance Th1-mediated immune responses. The virus utilizes serotype 5/35 for gene transfer, ensuring that antigens are released at the site of immune activation. The expression of the transgenes is controlled by a separate promoter, which is efficient in both tumor cells and stroma, while the virus's replication is confined to tumor cells through a specific deletion.

Experiments demonstrated that LOAd703 effectively killed tumor cells without harming healthy cells, as determined by an MTS assay. The virus was found to be as efficient as a comparable oncolytic virus lacking transgenes, indicating that the additional gene expression did not hinder its replication. In a xenograft model, repeated injections of LOAd703 controlled tumor growth and led to sustained complete responses, which were further improved by the addition of gemcitabine.

Furthermore, when human monocyte-derived dendritic cells were exposed to LOAd703, they expressed high levels of CD40L and 4-1BBL without being lysed. Instead, these cells matured, as evidenced by increased CD83 and IL12 expression. The inclusion of 4-1BBL in the virus significantly boosted the maturation of dendritic cells, resulting in higher levels of various immune-stimulating factors. LOAd703-transduced dendritic cells, when combined with CMV peptides, were also able to robustly expand antigen-specific T cells and NK cells.

The research concludes that LOAd703 is a promising new approach to immunostimulatory gene therapy that can initiate strong Th1 responses and eliminate pancreatic cancer in experimental settings. A clinical trial for LOAd703 in treating pancreatic cancer is currently in progress.