Improved experimental radioimmunotherapy of colon xenografts by combining 131I-CC49 and interferon-gamma.

Abstract

This study was designed to determine whether the ability of interferon-gamma to upregulate the expression of a human tumor antigen improved the therapeutic efficacy of a radionuclide-conjugated monoclonal antibody. 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-gamma. Antitumor effects of an 131I-labeled antitumor-associated glycoprotein-72 monoclonal antibody, CC49, were determined by measuring changes in tumor volumes in the respective groups of athymic mice. Interferon-gamma 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-gamma, which accounted for the enhanced tumor localization of 131I-CC49 in mice. That experimental model was used to examine the antitumor effects of combining interferon-gamma with 131I-CC49. Administration of 300 microCi of 131I-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 300 microCi of 131I-CC49 and interferon-gamma. In fact, the cytokine/radioimmunoconjugate combination eradicated any evidence of tumor in approximately 30 percent of the mice. The ability of interferon-gamma 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.