A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy.
A variety of observations have shown that carcinoembryonic antigen (CEA) is associated with growth and metastasis of cancers, including correlation of CEA serum levels with poor clinical outcome, mediation of cell-cell adhesion by CEA, and involvement of CEA in the immune recognition of tumors and apoptotic pathways. The purpose of this study was to investigate the effect that an anti-CEA monoclonal antibody (MAb) may have on the growth of medullary thyroid cancer (MTC), a CEA-expressing tumor, alone and in combination with chemotherapy. Antitumor effects were evaluated in a nude mouse-human MTC xenograft model. Using the TT MTC cell line grown s.c., we compared tumor growth in untreated mice with that of mice given the humanized anti-CEA MAb labetuzumab or an isotype-matched control MAb. The effects of time of administration post-tumor injection, MAb dose response, specificity of response, and combination with dacarbazine (DTIC) chemotherapy were studied. The humanized anti-CEA MAb, labetuzumab, has direct, specific, antitumor effects in this model, without conjugation to a cytotoxic agent. In addition, labetuzumab sensitizes these tumor cells to chemotherapy with an effective drug in this model, DTIC, without increased toxicity. Significant delays in tumor growth were caused by the MAb therapy or chemotherapy alone; however, the combination of these agents was significantly more effective than either agent given as a monotherapy or use of an irrelevant MAb in this model. The superiority of the combined modality treatment argues for the integration of CEA MAb therapy into chemotherapeutic regimens for MTC management and possibly other CEA-expressing neoplasms.
Stein
Rhona
R
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA. rstein@gscancer.org
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003606:Dacarbazine / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D002272:Carcinoembryonic Antigen; D003606:Dacarbazine