Definition

A genetically engineered oncolytic vaccinia viral (VV) vector expressing the human immunostimulating cytokine interleukin-12 (IL-12) and a full-length antibody directed against the human inhibitory T-cell-expressed receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CTLA4), with potential immune checkpoint inhibitory and antineoplastic activities. Upon intavenous administration, IL-12/anti-CTLA-4 monoclonal antibody-expressing oncolytic VV TG6050 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, 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 tumor cells. In addition, the expression of IL-12 promotes the activation of natural killer (NK) cells, which induces the secretion of interferon-gamma and a CTL-mediated response against uninfected tumor cells. This results in immune-mediated tumor cell death and further inhibition of tumor cell proliferation. The anti-CTLA-4 antibody released by the infected cells targets and binds to CTLA-4 expressed on T cells and inhibits the CTLA-4-mediated downregulation of T-cell activation, which promotes T-cell activation and further enhances a CTL-mediated anti-tumor immune response. CTLA-4, an inhibitory receptor and member of the immunoglobulin superfamily (IgSF), plays a key role in the downregulation of the immune system.