A phase I trial of retroviral BRCA1sv gene therapy in ovarian cancer.
Gene transfer of BRCA1sv (a normal splice variant of BRCA1) into ovarian cancer cells produces growth inhibition in vitro and tumor suppression in nude mouse xenografts. As an initial step toward gene replacement therapy for ovarian cancer, we conducted a Phase I trial to assess the pharmacokinetics and toxicity of i.p. BRCA1sv retroviral vector therapy. Following placement of an indwelling Port-a-Cath in patients, a dose escalation study was performed of four daily i.p. infusions spanning doses from 3 to 300 ml (i.e., 10(10) viral particles) at half-log intervals (23 cycles in 12 patients). Gene transfer and expression were documented by PCR, Southern blot, reverse transcription-PCR, and nuclease protection assays. Pharmacokinetics were assessed by PCR and Southern blots detecting vector DNA, and toxicity was evaluated by clinical exam and fluid analysis. Three of 12 patients developed an acute sterile peritonitis, which spontaneously resolved within 48 h. Plasma and peritoneal antibodies to the retroviral envelope protein were detected only in patients treated with the highest dose levels but not in others, despite repeat dosing for an interval of up to 4 months. Eight patients showed stable disease for 4-16 weeks, and three patients showed tumor reduction with diminished miliary tumor implants at reoperation (two patients) and radiographic shrinkage of measurable disease (one patient). The vector-related complication of peritonitis was observed in three patients but resolved quickly as in preclinical mouse studies. Ovarian cancer may provide an important model for retroviral gene therapy studies due to vector stability, minimal antibody response, and access to tumor by i.p. therapy.
Tait
D L
DL
Vanderbilt University Medical Center, Departments of Obstetrics and Gynecology, Cell Biology, Pathology, and Medicine, Nashville, Tennessee 37232-6838, USA.
Obermiller
P S
PS
Redlin-Frazier
S
S
Jensen
R A
RA
Welcsh
P
P
Dann
J
J
King
M C
MC
Johnson
D H
DH
Holt
J T
JT
D000328:Adult; D000368:Aged; D000818:Animals; D004279:DNA, Viral / Q000493:pharmacokinetics; D005260:Female; D019398:Genes, BRCA1; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D012086:Reoperation; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D004279:DNA, Viral