Improved experimental radioimmunotherapy of colon xenografts by combining¹³¹I-CC49 and Interferon-γ

Abstract

PURPOSE: This study was designed to determine whether the ability of interferon-γ to upregulate the expression of a human tumor antigen improved the therapeutic efficacy of a radionuclide-conjugated monoclonal antibody. METHODS: Tumor xenografts of the moderately differentiated human colon tumor cell line HT-29 were grown in athymic mice. Constitutive levels of the human tumor antigen, tumor-associated glycoprotein-72, were measured before and after treatment with interferon-γ. Antitumor effects of an¹³¹I-labeled antitumor-associated glycoprotein-72 monoclonal antibody, CC49, were determined by measuring changes in tumor volumes in the respective groups of athymic mice. RESULTS: Interferon-γ induced a time-dependent and dose-dependent increase in tumor-associated glycoprotein-72 expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous tumor-associated glycoprotein-72-positive tumor cell population in tumors isolated from mice treated for eight days with interferon-γ, which accounted for the enhanced tumor localization of¹³¹I-CC49 in mice. That experimental model was used to examine the antitumor effects of combining interferon-γ with¹³¹I-CC49. Administration of 300 μCi of¹³¹I-CC49 to mice bearing HT-29 tumors induced a transient suppression of tumor growth. Conversely, a long-term, sustained HT-29 tumor growth suppression was achieved in mice given 300μCi of¹³¹I-CC49 and interferon-γ. In fact, the cytokine/radioimmunoconjugate combination eradicated any evidence of tumor in approximately 30 percent of the mice. CONCLUSION: The ability of interferon-γ to enhance tumor-associated glycoprotein-72 expression substantially augmented the antitumor effects of the radioimmunoconjugate. Those observations provide additional argument for use of a radioimmunoconjugate in combination with a cytokine to improve tumor diagnosis and therapy.