Definition

A genetically engineered oncolytic herpes simplex virus type 1 (oHSV-1) expressing the human immunostimulating cytokine interleukin-12 (IL-12) and an antibody directed against the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279), with potential immune checkpoint inhibitory and antineoplastic activities. Upon intratumoral administration, oHSV-1 expressing IL-12 and anti-PD-1 antibody T3011 infects and replicates in tumor cells causing viral-mediated tumor cell lysis. The released virus particles, in turn, infect and replicate in neighboring tumor cells. Tumor antigens released from the lysed tumor cells also activate the immune system to induce a tumor-specific systemic immune and cytotoxic T-lymphocyte (CTL) response, thereby killing nearby non-infected tumor cells. In addition, oHSV-1 expressing IL-12 and anti-PD-1 antibody T3011 promotes the secretion of IL-12 and anti-PD-1 antibody by the tumor cells. IL-12 promotes the activation of natural killer cells, which induces both the secretion of interferon-gamma and a cytotoxic T-lymphocyte (CTL) response against the tumor cells. This results in both immune-mediated tumor cell death and further inhibition of tumor cell proliferation. Anti-PD-1 antibody targets, binds to and inhibits PD-1 and its downstream signaling pathways. This may restore immune function through the activation of T-cells and T-cell-mediated immune responses against tumor cells. PD-1, a transmembrane protein in the immunoglobulin superfamily (IgSF) expressed on T cells, functions as an immune checkpoint that negatively regulates T-cell activation and effector function when activated by its ligands programmed cell death-1 ligand 1 (PD-L1) or 2 (PD-L2); it plays an important role in tumor evasion from host immunity.