Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application.
Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the gamma134.5 gene are promising therapies for cancer. Deltagamma134.5 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 Deltagamma134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of gamma(1)34.5 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 Deltagamma134.5 oncolytic therapy.
Smith
Kerrington D
KD
MD Anderson Cancer Center, Department of Surgical Oncology, 1515 Holcombe Blvd. Unit 444, Houston TX 77030, USA. kdsmith@mdanderson.org
Shao
Michael Y
MY
Posner
Mitchell C
MC
Weichselbaum
Ralph R
RR
D000818:Animals; D045744:Cell Line, Tumor; D005838:Genotype; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D017384:Sequence Deletion / Q000235:genetics*
D020930:MAP Kinase Kinase Kinases