The objective of this proposal is to establish methods to reduce the toxicity to non-tumor tissue associated with radioimmunotherapy (RAIT) and thereby enhance the potential success of RAIT through dose intensification. The dose of 1-131-antibody that can be used for tumor therapy and the frequency at which radioantibody can be administered are limited currently by damage to hematopoietic cells, as measured by a significant and prolonged decline in circulating white blood cells (WBCs). This limitation of RAIT is similar to that observed with conventional chemo- or radiation therapy, but more complicated, in that RAIT involves a prolonged exposure to low levels of radiation. Our approach will be to use (a) immunomodulators such as interleukin-1 (IL-1) and granulocyte-macrophage colony stimulating factor (GM-CSF) to stimulate white blood cell production, and (b) an anti-antibody (second antibody) to enhance clearance of the primary radioantibody and thereby, reduce exposure time of radiosensitive non-tumor tissue. The efficacy of these agents will be evaluated as they are used individually or in combination to protect the tumor-bearing host from higher doses of radioantibody and/or multiple treatments with radioantibody. Anti-tumor activity of higher and/or more frequent doses of radioantibody will be assessed. The functional competence of WBC subpopulations (lymphocytes, neutophils and monocytes) will be compared in untreated, radioantibody-treated and immunomodulator/anti-antibody-treated mice. The model for these studies will be the well characterized GW-39 human colon carcinoma grown in the nude mouse. RAIT will be performed using an I-131-labeled intact antibody or F(ab')2 fragment directed against the carcinoembryonic antigen (CEA).
