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- B4125691f0b8b49895e72087fb7d9ff1b NCIT_P378 "NCI" @default.
- B4125691f0b8b49895e72087fb7d9ff1b type Axiom @default.
- B4125691f0b8b49895e72087fb7d9ff1b annotatedProperty IAO_0000115 @default.
- B4125691f0b8b49895e72087fb7d9ff1b annotatedSource NCIT_C179675 @default.
- B4125691f0b8b49895e72087fb7d9ff1b annotatedTarget "A genetically engineered oncolytic herpes simplex virus type 1 (oHSV-1) expressing the human immunostimulating cytokine interleukin (IL)-12, the immunostimulating cytokine IL-15 and its receptor alpha unit (IL-15Ra), and a blocking peptide directed against the immunosuppressive ligand programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274), with potential immune checkpoint inhibitory, immunostimulatory and antineoplastic activities. The blocking peptide is a fusion protein composed of the TF peptide, derived from fragments of human programmed cell death 1 (PD-1; PDCD1; CD279; programmed death-1) protein, fused to an immunoglobulin G4 (IgG4) Fc (TF-Fc). Upon intratumoral administration, oHSV-1 expressing IL-12, IL-15/IL-15Ra and PD-L1 blocking peptide VG161 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, IL-15/IL-15Ra and PD-L1 blocking peptide VG161 promotes the secretion of IL-12, IL-15/IL-15Ra and PD-L1 blocking peptide by the tumor cells locally in the TME. IL-12 promotes the activation of natural killer (NK) cells, which induces both the secretion of interferon-gamma and a CTL response against the tumor cells. IL-15 stimulates the proliferation of NK cells, CTLs and memory T-cells, which induces an anti-tumor immune response. These actions of the cytokines may increase tumor cell killing and decrease tumor cell proliferation. PD-L1 blocking peptide targets, binds to and inhibits PD-L1, preventing the binding and subsequent activation of its receptor, PD-1. This reverses T-cell inactivation caused by PD-L1/PD-1 signaling, increases T-cell expansion and enhances the CTL-mediated anti-tumor immune response. PD-L1, a transmembrane protein, is expressed on the surface of antigen presenting cells (APCs) and on many cancer cell types. PD-L1 binding to PD-1, a negative regulator of the immune system on activated T-cells, limits the expansion and survival of CD8+ T-cells, suppresses the immune system and results in immune evasion. IL-15Ra complexed with IL-15 increases IL-15 signaling and IL-15 half-life upon expression." @default.