) We propose the development of a vaccine to treat metastatic colon cancer using an adenovirus vector encoding the GA733 antigen that is widely expressed on human gastrointestinal malignancies. Passive immunization studies in humans has shown that this antigen is an effective target against which a therapeutic immune response can be generated. In animal models we have demonstrated that this same antigen will elicit both cellular and humoral immune responses when it is administered as a recombinant protein expressed by an adenovirus vector. Vaccination of animals with this vector (Ad.GA733) not only prevents the development of new tumors but leads to the regression of established tumors as well. Furthermore, an immune response can be generated against the murine homologue of GA733 antigen in mice, indicating that tolerance to this protein can be overcome by vaccination strategies. In this proposal we will test the safety of Ad.GA733 in a series of animal models to establish the safety of this vaccine. We will then conduct a phase I/II clinical trial to demonstrate the safety and immunologic efficacy of this approach in patients with early metastatic colon cancer. Patients will be vaccinated with a single dose of Ad.GA733 given intraperitoneally. They will then be monitored for the development of an antigen specific immune response. A subset of patients at each dose will be tested for evidence of antigen expression using peritoneal lavage to recover peritoneal macrophages and mesothelial cells. The immune response to GA733 antigen will be assessed by delayed-type hypersensitivity reaction to the purified GA733 antigen and by a series of in vitro tests. The latter will include ELISA assays to detect antibody to GA733 antigen, antibody binding to tumor cells, lymphocyte proliferation assays, and cytotoxic T cell assays. Patients will be enrolled in groups of six patients at each of five dose levels. This study will determine the dose limiting toxicity of this therapy and to assess at what dose an immune response to the tumor antigen occurs.
| Smith, J G; Raper, S E; Wheeldon, E B et al. (1997) Intracranial administration of adenovirus expressing HSV-TK in combination with ganciclovir produces a dose-dependent, self-limiting inflammatory response. Hum Gene Ther 8:943-54 |
| Eck, S L (1997) Future directions for the treatment of colorectal carcinoma. Hematol Oncol Clin North Am 11:795-810 |
