oncolytic herpes simplex virus-1 expressing anti-CTLA-4 antibody/CD40L/4-1BBL RP3

A genetically modified oncolytic viral strain of the herpes simplex type 1 (HSV-1) virus, expressing an antibody directed against the human inhibitory T-cell-expressed receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4;CTLA4), CD40 ligand (CD40L; CD154; TRAP; TNFSF5) and the co-stimulatory molecule tumor necrosis factor ligand superfamily (TNFSF) member 9 (TNFSF9; 4-1BBL) with potential oncolytic, immunostimulating and antineoplastic activities. Upon administration, the oncolytic HSV-1 expressing anti-CTLA-4 Antibody/CD40L/4-1BBL RP3 specifically 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. Oncolytic virus RP3 expresses a fusogenic protein, GALV-GP R-, for optimal tumor cell infection and killing. In addition, Oncolytic virus RP3 promotes the expression of anti-CTLA-4 antibody, CD40L and 4-1BBL by the tumor cells. 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. This leads to a CTL-mediated immune response against tumor cells. CTLA-4, an inhibitory receptor and member of the immunoglobulin superfamily (IgSF), plays a key role in the downregulation of the immune system. CD40L specifically binds to and activates CD40, a cell surface receptor that belongs to the tumor necrosis factor (TNF) receptor family and is expressed on various immune cells, such as B lymphocytes, monocytes, and dendritic cells (DCs). Activation of CD40 induces proliferation and activation of B lymphocytes, shifts the induction of suppressive macrophages towards immunostimulatory macrophages, activates monocyte-derived DCs (moDCs), and leads to the secretion of inflammatory cytokines, which activates the immune system to induce the proliferation and activation of CTLs against tumor cells. 4-1BBL binds to and subsequently induces the proliferation and activation of natural killer (NK) cells and T cells. This enhances the secretion of cytokine interferon-gamma (IFN-g) and further induces an anti-tumor immune response.