title: A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I trial.
abstract: The purpose of this Phase I study was to determine the feasibility of using an anti-erbB-2-encoding adenovirus (Ad21) to treat erbB-2-overexpressing ovarian cancer. Recurrent ovarian cancer patients were treated i.p. with Ad21 in dosages ranging from 1 x 10(9) to 1 x 10(11) pfu. Patients were monitored after treatment for evidence of clinical toxicity and efficacy. Peritoneal aspirates and serum samples were obtained to assess for evidence of gene transfer/expression, for generation of wild-type vector, and antiadenoviral humoral response. Fifteen patients were treated per study specifications. Treatment-specific grade 1/2 fever was experienced by 9 of 15 (60%) patients. Other transient grade 1/2 constitutional, pain, and gastrointestinal symptoms were also experienced. No dose-limiting vector-related toxicity was experienced. Of 13 patients evaluable for response, 5 (38%) had stable disease and 8 (61%) had evidence of progressive disease. One patient with nonmeasurable disease normalized her CA125 at the 8-week evaluation, and one patient with nonmeasurable disease remained without clinical evidence of disease for 6 months after treatment. PCR analysis of peritoneal aspirates demonstrated the presence of Ad21 in 84.6%, 84.6%, and 61.6% of evaluable specimens at days 2, 14, and 56 after treatment, respectively. No wild-type virus was detected. Reverse transcription-PCR analysis demonstrated expression of the anti-erbB-2 sFv-encoding gene in 10 of 14 evaluable patients at day 2. Five of six evaluable patients had an increase in antiadenovirus antibody titer. This study suggests that adenoviral-mediated gene therapy using an anti-erbB-2-directed intrabody is feasible in the context of human ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, 35233-7333, USA. rdalvarez@aol.com
authors.forename: R D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: M N
authors.initials: MN
authors.lastname: Barnes
authors.forename: J
authors.initials: J
authors.lastname: Gomez-Navarro
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: T V
authors.initials: TV
authors.lastname: Strong
authors.forename: W
authors.initials: W
authors.lastname: Arafat
authors.forename: R B
authors.initials: RB
authors.lastname: Arani
authors.forename: M R
authors.initials: MR
authors.lastname: Johnson
authors.forename: B L
authors.initials: BL
authors.lastname: Roberts
authors.forename: G P
authors.initials: GP
authors.lastname: Siegal
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000368:Aged; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D018734:Genes, erbB-2 / Q000276:immunology; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000912:Antibodies, Neoplasm; D007128:Immunoglobulin Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases