Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses.
BACKGROUND
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is refractory to current treatment modalities. Oncolytic herpes simplex viruses (HSV) used for gene therapy are genetically engineered, replication-competent viruses that selectively target tumor cells while sparing normal host tissue. The localized nature, the potential accessibility and the relative lack of distant metastasis make MPM a particularly suitable disease for oncolytic viral therapy.


METHODS
The infectivity, selective replication, vector spread and cytotoxic ability of three oncolytic HSV: G207, NV1020 and NV1066, were tested against eleven pathological types of MPM cell lines including those that are resistant to radiation therapy, gemcitabine or cisplatin. The therapeutic efficacy and the effect on survival of NV1066 were confirmed in a murine MPM model.


RESULTS
All three oncolytic HSV were highly effective against all the MPM cell lines tested. Even at very low concentrations of MOI 0.01 (MOI: multiplicity of viral infection, ratio of viral particles per cancer cell), HSV were highly effective against MPM cells that are resistant to radiation, gemcitabine and cisplatin. NV1066, an oncolytic HSV that expresses green fluorescent protein (GFP), was able to delineate the extent of the disease in a murine model of MPM due to selective infection and expression of GFP in tumor cells. Furthermore, NV1066 was able to reduce the tumor burden and prolong survival even when treatment was at an advanced stage of the disease.


CONCLUSIONS
These findings support the continued investigation of oncolytic HSV as potential therapy for patients with therapy-resistant MPM.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Prasad S
PS
Adusumilli
Brendon M
BM
Stiles
Mei-Ki
MK
Chan
Michael
M
Mullerad
David P
DP
Eisenberg
Leah
L
Ben-Porat
Rumana
R
Huq
Valerie W
VW
Rusch
Yuman
Y
Fong
D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010997:Pleural Neoplasms / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D014183:Transplantation, Heterologous; D014779:Virus Replication
D049452:Green Fluorescent Proteins