drug_type
RELEVANT_DRUG
intervention_type
Biologic gene therapy vector
drug_description
Non-replicating, off-the-shelf gene therapy vector that delivers HSV-enhanced thymidine kinase (suicide gene) and human GM-CSF to tumors, making transduced cells susceptible to valganciclovir and enhancing antitumor immune activation via myeloid APC recruitment.
nci_thesaurus_concept_id
C176770
nci_thesaurus_preferred_term
HSV- thymidine Kinase-m2/hGM-CSF Genes-encoding GEN2
nci_thesaurus_definition
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.
drug_category
GENE THERAPY
drug_class
Gene therapy
drug_delivery_route
Intravenous infusion, Intratumoral injection
drug_mechanism_of_action
Non-replicating gene therapy vector that transduces tumor cells to express HSV-enhanced thymidine kinase and human GM-CSF. After vector delivery, oral valganciclovir is phosphorylated by HSV-tk in transduced cells to ganciclovir triphosphate, which inhibits DNA synthesis and kills those tumor cells. Resultant antigen release plus locally expressed GM-CSF recruits and activates myeloid antigen-presenting cells, enhances antigen presentation, and promotes cytotoxic T-cell (and NK)–mediated antitumor immunity.
drug_name
GEN2
nct_id_drug_ref
NCT06391918