A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene.
OBJECTIVE
HER-2/neu oncogene is overexpressed in 10-30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients.


METHODS
A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m(2), given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity


RESULTS
Fifteen patients, with a median age of 57 years (range, 43-81) were recruited. Three (1.8 mg DNA/m(2)), 4 (3.6 mg DNA/m(2)), and 8 patients (7.2 mg DNA/m(2)) received i.p. E1A. A total of 91 infusions (range, 1-18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m(2). E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity.


CONCLUSIONS
I.P. EIA-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.
Madhusudan
Srinivasan
S
Cancer Research UK Medical Oncology Unit, The Churchill Hospital, Oxford, UK.
Tamir
Ayala
A
Bates
Nicholas
N
Flanagan
Elizabeth
E
Gore
Martin E
ME
Barton
Desmond P J
DP
Harper
Peter
P
Seckl
Michael
M
Thomas
Hilary
H
Lemoine
Nicholas R
NR
Charnock
Mark
M
Habib
Nagy A
NA
Lechler
Robert
R
Nicholls
Joanna
J
Pignatelli
Massimo
M
Ganesan
Trivadi S
TS
D015746:Abdominal Pain / Q000209:etiology; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001247:Asthenia / Q000209:etiology; D015331:Cohort Studies; D005260:Female; D005334:Fever / Q000209:etiology; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000737:chemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016896:Treatment Outcome
D017500:Adenovirus E1A Proteins; D008055:Lipids; D018719:Erb-b2 Receptor Tyrosine Kinases