Delivery of herpes simplex thymidine kinase bystander effect by engineered human mesothelial cells for the treatment of ovarian cancer.
BACKGROUND
Resistance to conventional chemotherapy is a major clinical problem for ovarian cancer, and long-term survival for patients with advanced-stage disease is rare. Other therapeutic strategies, such as gene therapy, have been explored but several limitations exist, which include low viral vector transduction efficiency, host immune response to the vector, and vector toxicity.


METHODS
We developed a cell-based therapy that exploits human mesothelial cells to deliver anticancer modalities for treatment of ovarian cancer. As a proof of concept, we genetically engineered mesothelial with the herpes simplex virus thymidine kinase/ganciclovir (HSVTK/GCV) system to deliver cytotoxicity to human ovarian cancer cells. This system is well characterized, and has been widely used in different gene-therapy based strategies.


RESULTS
Our results demonstrate that HSVTK-modified mesothelial cells are sensitive to GCV killing in vitro and support the HSVTK bystander effect. Engineered mesothelial cells can deliver the HSVTK bystander effect to human ovarian cancer cell-lines, as well as to primary ovarian cancer cells. A significant reduction of tumor growth and prolongation of survival in s.c. and i.p. xenograft mouse models of ovarian cancer are obtained with as little as 1% of HSVTK-expressing mesothelial cells. Intraperitoneal administration of HSVTK-expressing mesothelial cells in an established mouse model of ovarian cancer results in a statistically significant prolonged survival of treated animals. Importantly, distribution studies showed that mesothelial cells localize preferentially to tumor sites.


CONCLUSIONS
Our study demonstrates the feasibility of using a mesothelial cell-based therapy for treatment of ovarian cancer, and suggests that this strategy should be further explored.
Rancourt
C
C
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Canada.
Bergeron
C
C
Lane
D
D
Garon
G
G
Piché
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D024201:Bystander Effect; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation; D018920:Coculture Techniques; D018031:Connexin 43 / Q000032:analysis / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006651:Histocytochemistry; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D018031:Connexin 43; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir