Definition

A genetically modified oncolytic virus (OV) composed of a replication competent orthopoxviral chimera engineered to express the human sodium iodine symporter (hNIS) and a human monoclonal antibody directed against the immunosuppressive ligand and immune checkpoint inhibitor programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274), with potential oncolytic, immunostimulating and antineoplastic activities that can be used for radioimaging upon positron emission tomography (PET) and radiotherapeutic applications. Upon subcutaneous (SC) intratumoral (IT) administration of the oncolytic virus CF33-expressing hNIS/anti-PD-L1 antibody, the oncolytic virus 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. In addition, the anti-PD-L1 antibody produced by the infected tumor cells targets and binds to PD-L1, blocking its binding to and activation of its receptor programmed cell death 1 (PD-1; cluster of differentiation 279; CD279), a transmembrane protein and negative regulator of the immune system, expressed on activated T cells. This reverses T-cell inactivation caused by PD-1/PD-L1 signaling and enhances the CTL-mediated anti-tumor immune response against PD-L1-expressing tumor cells, thereby further killing tumor cells. Upon subsequent administration of certain iodine-containing imaging agents, hNIS expression by the infected tumor cells allows visualization and tracking of viral biodistribution, and analysis and quantification of CF33-infected tumor cells by PET. Also, administration of iodine I 131 results in its uptake by hNIS-expressing tumor cells, which may result in the selective accumulation of a cytotoxic dose of radiation in tumor cells while sparing adjacent normal tissue.