Gene therapy of ovarian cancer with IFN-alpha-producing fibroblasts: comparison of constitutive and inducible vectors.
Ovarian cancer represents a malignancy suitable for cell and gene therapy approaches owing to its containment within the peritoneal cavity, even at advanced tumor stages. As regulation of transgene expression would be preferable for conducting clinical trials for reasons of safety, we investigated whether intraperitoneal (i.p.) administration of retroviral vector-transduced fibroblasts encoding murine interferon-alpha (IFN-alpha) could have therapeutic activity, and compared its effect with the antitumor effects of fibroblasts producing IFN-alpha under a rapamycin analogue (AP21967)-inducible promoter. Human and murine fibroblasts were recruited into the solid component of transplantable ovarian cancer-grown i.p. in severe combined immunodeficiency mice. Multiple administrations of fibroblasts producing IFN-alpha in a constitutive manner showed therapeutic efficacy, leading to significant prolongation of survival in the majority of animals, associated with inhibition of tumor angiogenesis. Compared to cells transduced by the constitutive vector, fibroblasts transduced by the inducible vector released twofold higher IFN-alpha levels in vitro, following induction by AP21967, and production of the cytokine was under pharmacologic control both in vitro and in vivo. However, these cells elicited only modest therapeutic effects in vivo. Overall, these findings indicate that intracavitary IFN-alpha gene therapy using engineered fibroblasts requires sustained production of IFN-alpha to achieve durable antitumor effects.
Indraccolo
S
S
Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy. stefano.indraccolo@unipd.it
Moserle
L
L
Tisato
V
V
Gola
E
E
Minuzzo
S
S
Roni
V
V
Persano
L
L
Chieco-Bianchi
L
L
Amadori
A
A
D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000637:transplantation*; D005470:Fluorometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D016898:Interferon-alpha / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D016209:Interleukin-8 / Q000032:analysis; D051379:Mice; D018613:Microscopy, Confocal; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D016898:Interferon-alpha; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A