NOVEL APPROACHES TO TUMOR-DETECTION AND THERAPY USING A COMBINATION OF MONOCLONAL-ANTIBODY AND CYTOKINE

Cytokine-based tumor antigen augmentation is one of the approaches res earchers and clinicians are using to improve the effectiveness of MAb- directed tumor diagnosis and therapy. Other efforts encompass the use of dose-fractionation for multiple administrations of radioimmunoconju gates, exploitation of genetic engineering to construct antibody molec ules with specific biological properties (i.e., altered pharmacokineti cs, activation of cellular immune responses, etc.) and use of MAb-dire cted conjugates that can enhance tumor MAb uptake by altering tumor pe rfusion (7,19). The studies summarized here as well as those from othe r laboratories have served as the framework for clinical investigation s designed to determine the effectiveness of the interferons and other differentiation-inducing agents to alter the tumor antigen phenotype in patients. In an earlier study, patients given IFN-alpha had improve d tumor uptake of an antimelanoma MAb (20). Subsequently, we reported that i.p. IFN-gamma administration substantially upregulated TAG-72 an d CEA on the surface of human tumor cells isolated from malignant asci tes (21). A seminal investigation showed significant increase of TAG-7 2 and CEA levels in tumor biopsies from patients diagnosed with colore ctal carcinoma and given systemic IFN-alpha (22). Those studies led to a clinical trial in which late stage breast cancer patients were admi nistered interferon in combination with therapeutic doses of CC49. Som e clinical responses were observed, however, the cytokine and MAb comb ination may have also enhanced marrow toxicity. Future studies will co ntinue to evaluate the ability to enhance tumor antigen expression in the context of genetically engineered MAbs designed to minimize normal organ toxicity.