Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application

Abstract

Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the γ134.5 gene are promising therapies for cancer. Δγ134.5 mutant replication and cytolysis is tumor cell type specific and severely attenuated in normal tissues. The basis for attenuation lies in the activation of the protein kinase R (PKR)-mediated host cellular defense pathway, which inhibits protein synthesis in infected cells. Tumor cells which overexpress MAPK kinase (MEK) activity support robust replication of Δγ134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of γ134.5 mutants may allow selective targeting and destruction of metastases from a broad range of solid human tumors that overexpress MEK. Barriers to systemic HSV-1 oncolytic therapy include innate immunity, adaptive immunity and hepatic adsorption. Immunomodulating agents may overcome innate immunity to HSV-1-based vectors. Preclinical data combined with the pervasiveness of HSV-1 despite widespread immunity suggest that preexisting immunity may not eliminate oncolytic efficacy. In the future, biopsy-determined tumor MEK status may select patients for Δγ134.5 oncolytic therapy.