CXCR3/IL-12/TGFb1 inhibitor engineered oncolytic vaccinia Virus VET3-TGI

An oncolytic vaccinia virus (VV) genetically engineered to express C-X-C chemokine receptor type 3 (CXCR3), the human pro-inflammatory cytokine interleukin-12 (IL-12), and an inhibitor of transforming growth factor (TGF)-beta 1 (TGFb1; TGF-b1), with potential immunomodulating and antineoplastic activities. Upon administration of CXCR3/IL-12/TGFb1 inhibitor engineered oncolytic VV VET3-TGI, the virus preferentially targets, infects and replicates in tumor cells, particularly tumor cells expressing CXCR3 ligands, causing oncolysis. In turn, the lysed tumor cells release various tumor-associated antigens (TAAs), which induce an immune response against the tumor cells. In addition, CXCR3/IL-12/TGFb1 inhibitor engineered oncolytic VV VET3-TGI promotes the secretion of IL-12 and the TGFb1 inhibitor in the tumor microenvironment (TME). IL-12 activates natural killer cells (NKs), induces the secretion of interferon-gamma (IFNg) and promotes CD8 cytotoxic T-lymphocyte (CTL) responses against tumor cells, which may result in immune-mediated tumor cell death and inhibition of tumor cell proliferation. The inhibition of TGFb1 prevents TGFb1-mediated signaling. This abrogates TGFb1-mediated immunosuppression, enhances anti-tumor immunity in the TME and further promotes CTL-mediated immune response against tumor cells. The TGF-beta signaling pathway is often deregulated in tumors and plays a key role in immunosuppression in the TME. TGFb1 is the predominant isoform in many tumors.