A variety of strategies including mutation compensation, molecular chemotherapy and genetic immunopotentiation have been developed to accomplish gene therapy for cancer. The applicant has developed a novel strategy that has recently been developed based upon the intracellular expression of single-chain antibodies (sFv) directed against the erbB-2 oncogene product. Employing this methodology, targeted ablation of the erbB-2 gene product in erbB-2 overexpressing ovarian cancer cells has been accomplished in in vivo and in vitro experiments. This has resulted in dramatic alterations of the malignant cellular phenotype in transfected cells resulting in abrogation of tumorigenicity and induction of apoptosis. Thus, this application seeks to develop this method of anti-cancer gene therapy as an experimental therapeutic for ovarian carcinoma, a malignancy commonly diagnosed in advanced stages and associated with a poor prognosis. Specifically, this application intends to determine 1) the maximally tolerated single dose, 2) the maximally tolerated number of cycles, 3) the spectrum of toxicities encountered with, 4) the safety of administration of and, 5) antitumor activity at the molecular level of recombinant adenovirus encoding an anti-erbB-2 single chain antibody gene in previously treated ovarian and extra-ovarian cancer patients. To achieve these specific aims, this application includes a human gene therapy protocol for ovarian and extra-ovarian cancer patients with persistent or recurrent disease. Two Phase I studies will be performed to determine the optimal dose and schedule of this novel therapeutic and its associated clinical toxicity. Additionally, safety studies will be performed in the context of these trials to determine if the viral vector employed elicits a host immune response, is expressed in transduced tumor cells, and propagates or replicates in the target cells. Lastly, molecular efficacy studies will be performed to determine if, in the context of human disease, the anti-sFv gene antibody transfects targeted ovarian cancer cells and results in decreased expression of the erbB-2 gene product and decreased cellular proliferation.
| Alvarez, R D; Barnes, M N; Gomez-Navarro, J et al. (2000) A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I trial. Clin Cancer Res 6:3081-7 |
| Vanderkwaak, T J; Wang, M; Gomez-Navarro, J et al. (1999) An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches. Gynecol Oncol 74:227-34 |
| Wright, M; Grim, J; Deshane, J et al. (1997) An intracellular anti-erbB-2 single-chain antibody is specifically cytotoxic to human breast carcinoma cells overexpressing erbB-2. Gene Ther 4:317-22 |
| Deshane, J; Siegal, G P; Wang, M et al. (1997) Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy. Gynecol Oncol 64:378-85 |
