oncolytic HSV-1-expressing IL-12 and anti-PD-1 antibody MVR-C5252

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 into the glioma, oHSV-1 expressing IL-12 and anti-PD-1 antibody MVR-C5252 specifically infects and replicates in glioma cells causing viral-mediated glioma cell lysis. The released virus particles, in turn, infect and replicate in neighboring glioma cells, thereby further killing 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 glioma cells. In addition, as MVR-C5252 carries exogenous genes, it is also able to express IL-12 and anti-PD-1 antibody and are released by the infected cells, both of which are able to promote an immune response in the tumor microenvironment (TME). 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 uninfected glioma cells. This results in both immune-mediated tumor cell death and further inhibition of tumor cell proliferation. The 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.