HSV-thymidine kinase-m2 and hGM-CSF genes-encoding GEN2

A gene therapy agent composed of a vector expressing a mutated form of the herpes simplex virus thymidine kinase (HSV-tk) gene and the human cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, with potential immunostimulating and antineoplastic activities. Upon administration, the HSV-thymidine kinase-m2/hGM-CSF genes-encoding GEN2 selectively infects tumor cells and expresses HSV-tk-m2 and GM-CSF. Subsequent administration of a synthetic acyclic guanosine analog, such as valganciclovir, allows the activation of this prodrug by HSV-tk to form ganciclovir. Once phosphorylated intracellularly, ganciclovir triphosphate competitively inhibits deoxyguanosine triphosphate (dGTP) incorporation into DNA and inhibits DNA synthesis. This kills the tumor cells expressing HSV-tk. The release of tumor-associated antigens (TAA) by dying tumor cells may then stimulate an antitumor cytotoxic T-lymphocyte (CTL) response, directed against any remaining tumor cells. The expressed GM-CSF enhances antigen presentation, promotes natural killer (NK) cell-mediated killing and causes a CTL response against tumor cells, resulting in an immune-mediated tumor cell death.