Selected cytokines augment the expression of tumor associated and major histocompatibility antigens on the surface of human tumor cells as well as induce the proliferation/maturation of antigen-specific cytotoxic lymphoid cells. The ability to exploit these cytokine actions may be an important component to improve tumor recognition by the humoral and/or cellular components of the immune system. We have reported that type I and II interferons can increase the expression of two human tumor antigens, tumor associated glycoprotein 72 (TAG-72) and carcinoembryonic antigen (CEA). Gamma-Interferon (IFN-g) and `- interferon increase the synthesis of TAG-72 and CEA in human tumor cell lines and when administered to mice bearing human tumor xenografts. Coupled with the use of an anti-TAG-72 single chain binding protein the interferon-mediated effects have led to an improved experimental immunoscintigraphy as well as tumor detection using a gamma-detecting hand held probe. Moreover, improved radioimmunotherapy was achieved when a radionuclide conjugated-MAb was administered with an antigen upregulation schema. Those findings formed the framework for subsequent clinical studies designed to determine the ability of interferon to upregulate tumor antigen expression. Initial studies showed that intracavitary IFN-g administration to patients with metastatic carcinoma substantially upregulated TAG-72 and CEA expression on human carcinoma cells isolated from patients' ascites. More recent collaborative studies provided further evidence that systemic IFN- administration increased TAG-72 and CEA in colonoscopic biopsies taken from patients with confirmed colon carcinoma, as well as enhanced localization of a radioimmunoconjugate in breast tumor biopsies. In addition to being a target for MAb-based immunotherapy, the cDNA for CEA has been incorporated into a vaccinia virus genome and the recombinant vaccinia virus-CEA construct (rV-CEA) has been used to generate T cell dependent cytotoxicity against CEA in an active immunotherapy experimental model. Our studies have shown that IL-2 administration with rV-CEA stimulates CEA-specific T cell proliferation as well as increases T cell cytotoxicity of CEA expressing mouse colon carcinoma cells. Studies on the use of other cytokines, administered either systemically, or via a recombinant pox virus vector, to enhance the immunogenicity of recombinant vaccines containing tumor antigen genes, are in progress.
