oncolytic HSV-1 expressing anti-PD-1 scFv-Fc/TGFbRII decoy/IL-12 STI-1386

A second-generation, genetically engineered oncolytic herpes simplex virus type 1 (oHSV-1) expressing a single-chain variable fragment (scFv)-Fc targeting the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279), a human transforming growth factor beta receptor 2 (TGFbRII) decoy and the human immunostimulating cytokine interleukin-12 (IL-12), with potential immune checkpoint inhibitory, immunostimulatory and antineoplastic activities. Upon administration, oHSV-1 expressing anti-PD-1 scFv-Fc/TGFbRII decoy/IL-12 STI-1386 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 anti-PD-1 scFv-Fc/TGFbRII decoy/IL-12 STI-1386 promotes the secretion of anti-PD-1 scFv-Fc, TGFbRII decoy and IL-12 by the tumor cells. The anti-PD-1 scFv-Fc 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. The TGFbRII decoy targets and binds to TGF-beta and prevents the activation of TGF-beta-mediated signaling pathways in the tumor microenvironment (TME). This abrogates the TGF-beta-mediated immunosuppression in the TME. TGF-beta, a pro-inflammatory mediator, is upregulated in certain types of cancers and is involved in cancer cell proliferation, tumor progression, migration and invasion, and the suppression of the immune response. 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. This results in both immune-mediated tumor cell death and further inhibition of tumor cell proliferation.