title: Improved radioimmunotherapeutic efficacy of an anticarcinoma monoclonal antibody (131I-CC49) when given in combination with gamma-interferon.
abstract: The moderately differentiated human colon tumor cell line, HT-29, constitutively expresses low levels of the high molecular weight mucin, tumor-associated glycoprotein 72 (TAG-72), and the M(r) 180,000 carcinoembryonic antigen (CEA) when grown as s.c. tumors in athymic mice. We report that the in vivo administration of gamma-interferon (IFN-gamma) resulted in a time- and dose-dependent increase in both TAG-72 and CEA expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous TAG-72-positive tumor cell population after IFN-gamma. Furthermore, both anti-TAG-72 and anti-CEA monoclonal antibodies (MAbs) showed enhanced localization to the HT-29 tumors in mice treated with IFN-gamma. Using that experimental model, subsequent studies presented evidence showing that the combination of IFN-gamma with 131I-CC49, an anti-TAG-72 MAb, resulted in a statistically significant improvement in therapeutic efficacy when compared with 131I-CC49 alone. For example, treatment with 300 microCi of 131I-CC49 initially suppressed HT-29 tumor growth; however, that reduction in tumor growth was transient as evidenced by the emergence of additional tumor growth at later time points. In contrast, an 8-day treatment with IFN-gamma in combination with 300 microCi 131I-CC49 resulted in sustained suppression of HT-29 tumor growth. Thus, IFN-gamma in vivo can substantially increase the TAG-72 expression in human colon tumor xenografts which leads to an increased tumor localization of anti-TAG-72 MAbs and seems to be responsible for the enhanced antitumor effects when IFN-gamma was combined with 131I-CC49. The results provide further evidence for including a biological response modifier, such as IFN-gamma, which can increase the expression of specific tumor antigens (i.e., TAG-72 and CEA) subsequently leading to a dramatic improvement in the antitumor efficacy of a radionuclide-conjugated MAb.
authors.affiliation: Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
authors.forename: J W
authors.initials: JW
authors.lastname: Greiner
authors.forename: C D
authors.initials: CD
authors.lastname: Ullmann
authors.forename: C
authors.initials: C
authors.lastname: Nieroda
authors.forename: C F
authors.initials: CF
authors.lastname: Qi
authors.forename: D
authors.initials: D
authors.lastname: Eggensperger
authors.forename: S
authors.initials: S
authors.lastname: Shimada
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: J
authors.initials: J
authors.lastname: Schlom
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000502:physiology; D002272:Carcinoembryonic Antigen / Q000502:physiology; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; C069631:TAG 12; D007371:Interferon-gamma