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Carcinoembryonic Antigen Expression of Resurgent Human Colon Carcinoma after Treatment with Therapeutic Doses of ⁹⁰Y--Carcinoembryonic Antigen Monoclonal Antibody¹

Divisions of Pathology [J. M. E., B. F., H. B.], Radiation Oncology [J. Y. C. W.], Surgery [J. A. K., J. D. B.], and Immunology [J. E. S.], City of Hope National Medical Center, Duarte, California 91010 and Hybritech Inc., [P. M. W.] San Diego, California 92126

We have previously shown that the colon carcinoma (LS174T) xenografts that emerged shortly after radioimmunotherapy with ⁹⁰Y-labeled anti-CEA monoclonal antibody (MAb) ZCE025 lacked significant expression of CEA in comparison with the untreated tumors. The present study was designed to establish if the immunophenotype of the treated tumors was the result of CEA specific therapy and if the effect was permanent. Athymic mice bearing LS174T tumors were treated either with 120 µCi of ⁹⁰Y-ZCE025, an equal dose of ⁹⁰Y-96.5 (nonspecific MAb), or received no treatment. When the treated tumors grew to approximately 1.5 cm in diameter (6 weeks after therapy), they were resected and aliquoted to be transplanted to other mice, plated in tissue culture, fixed in formalin, and homogenized for CEA quantitation. The procedure was repeated 3 times (a total of 4 months after treatment). The CEA content was evaluated 2 and 6 weeks after therapy and when the tumors were transplanted. We confirmed a 4-fold decrease of CEA in the resurgent tumors 6 weeks after specific ⁹⁰Y-ZCE025 therapy, which was twice the decrease experienced by the tumors treated with nonspecific ⁹⁰Y-96.5, indicating substantial and specific killing of CEA-expressing cells. The CEA content slowly but progressively increased with each new pass of the tumor in the mice, reaching approximately one-half the value of the controls at the end of the study. The resurgent tumors were also studied by immunohistochemistry with MAbs detecting different epitopes of CEA, keratin, TAG-72, and epithelial membrane antigen to evaluate possible additional immunophenotypic changes induced by radioimmunotherapy. Only the expression of TAG-72 (recognized by MAb B72.3) increased immediately after therapy, but it returned to the original levels by the end of the study. These results suggest that: (a) specific radioimmunotherapy with ⁹⁰Y-ZCE025 selectively kills cells that express higher levels of CEA; (b) the immunophenotype of the surviving fraction of the tumor appears to slowly revert to its original form; and (c) other tumor markers unrelated to CEA can also be affected. These observations have important implications for the design of radioimmunotherapy trials.

¹ Supported by Program Project Grant CA 43904 and Cancer Center Core Grant CA 33572. Presented in part at the "Fifth International Conference on Monoclonal Antibody Immunoconjugates for Cancer," March 15–17, 1990, San Diego, CA.

² To whom requests for reprints should be addressed.

Received 12/ 7/90. Accepted 5/ 1/91.

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