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An oncolytic vaccinia virus (VV; VACV) genetically engineered to express an Fms-like tyrosine kinase 3 (Flt3) ligand, an antibody directed against the human T-cell-expressed receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the human pro-inflammatory cytokine interleukin-12 (IL-12), with potential immunomodulating and antineoplastic activities. Upon administration of the Flt3 ligand/anti-CTLA-4 antibody/IL-12 engineered oncolytic VV RIVAL-01, the virus preferentially targets, infects and replicates in tumor cells, 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, the Flt3 ligand, the anti-ctla-4 antibody and IL-12 are expressed by the VV in the cancer cells and may activate the immune system within the tumor microenvironment (TME), thereby stimulating both innate and adaptive immune responses. The anti-CTLA-4 antibody targets and binds to CTLA-4 expressed on T-cells and inhibits the CTLA-4-mediated downregulation of T-cell activation, which promotes T-cell activation. Flt3 ligand binds to the Flt3 tyrosine kinase receptor and promotes Flt3 signaling which plays an important role in expanding the population of antigen-presenting dendritic cells (DCs). IL-12 activates natural killer cells (NKs), induces the secretion of interferon-gamma and promotes CD8 cytotoxic T-cell responses against tumor cells, which may result in immune-mediated tumor cell death and inhibition of tumor cell proliferation.
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