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A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I
R D Alvarez1, M N Barnes, J Gomez-Navarro
1Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, 35233-7333, USA. rdalvarez@aol.com
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.
Insights
This Phase I study found adenoviral gene therapy feasible for ovarian cancer. An anti-erbB-2 adenovirus (Ad21) showed gene transfer and expression with manageable toxicity in recurrent ovarian cancer patients.
Area of Science:
- Oncolytic Virotherapy
- Gene Therapy
- Ovarian Cancer Research
Background:
- Ovarian cancer often overexpresses the erbB-2 receptor.
- Novel therapeutic strategies are needed for recurrent ovarian cancer.
- Adenovirus vectors offer potential for targeted gene delivery.
Purpose of the Study:
- To assess the feasibility of adenoviral gene therapy for erbB-2-overexpressing ovarian cancer.
- To evaluate the safety and tolerability of an anti-erbB-2 adenovirus (Ad21).
- To determine preliminary efficacy and biological activity of Ad21 in patients.
Main Methods:
- Phase I clinical trial involving recurrent ovarian cancer patients.
- Intraperitoneal administration of Ad21 at escalating doses (1x10^9 to 1x10^11 pfu).
- Monitoring for toxicity, clinical response, gene transfer (PCR), gene expression (RT-PCR), and immune response.
Main Results:
- Ad21 gene transfer detected in 84.6% of specimens at day 2.
- Gene expression confirmed in 10/14 evaluable patients.
- Manageable toxicity with transient fever and constitutional symptoms; no dose-limiting toxicity.
- Preliminary signs of efficacy including stable disease in 38% and normalization of CA125 in one patient.
Conclusions:
- Adenoviral-mediated gene therapy with an anti-erbB-2 intrabody is feasible in ovarian cancer.
- Ad21 demonstrates successful gene transfer and expression in vivo.
- Further investigation in larger trials is warranted to establish therapeutic benefit.