Immunomagnetic and pharmacologic purging of tumor-involved bone marrow for patients undergoing regimens of high-dose chemotherapy and autologous bone marrow support
Pap, Stephen A.
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Autologous Bone Marrow Transplantation (ABMT) provides a way to rescue the hematopoietic system in patients receiving high dose chemotherapy. Solid tumors like lung and breast cancer are the targets for new therapies that involve high dose chemotherapy with AMBT due to their growth and pathologic characteristics. Reinfusion of bone marrow with metastatic neoplastic cells could also seed viable tumor cells, and thus be a reason for treatment failure, restricting high-dose chemotherapy with bone marrow support to patients whose marrow is morphologically free of tumor cells. The use magnetic beads for physical separation of tumor from normal cells and the use of a toxin delivered by a monoclonal antibody are examined as two purging methods for treatment. The use of magnetic beads conjugated with specific antibodies (SM1, LAM2 and LS1) against tumor antigens to purge 2-3 logs of Small Cell Lung Cancer (SCLC) contamination from bone marrow is demonstrated. Optimal performance calls for short double exposure to anti-tumor cell-antigen monoclonal antibodies, followed by exposure to magnetic beads coated with antibodies specific for the monoclonal anti-SCLC antibodies, maintaining a bead-to-cell ratio of 10:1 to 100:1. Specific toxin delivery to three breast cancer cell lines (ZR-75, BT20 and MCF7) expressing the DF3 antigen was demonstrated by the use of DF3 immunotoxin (DF3-IT). The optimal concentration of the DF3-IT immunotoxin for highest tumor kill was shown to be 1x1Q-9 M, but this caused a loss of bone marrow progenitor cell colonies of about 30%. Both methods are limited chiefly by the level of antigen expression in the target tumor cells. The purging efficiency could be improved by targeting a wider range of antigens or by inducing higher levels of antigen expression. From the clinical perspective, the advantages and need for purging involved bone marrow to bring about substantially improved curative strategies remains a question still unanswered.
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