The goal of this application is to use morphological and biochemical approaches to identify secondary end-organ toxicity, e.g. gastrointestinal, hepatic, renal and cardiopulmonary, associated with different radionuclides (131I, 90Y, 188Re) and different forms of antibody (intact, bivalent and monovalent fragments) and then develop methods to overcome this secondary normal tissue injury. Initial studies focused on the primary hematopoietic toxicity induced by radioimmunotherapy (RAIT) and were first to show successful reduction of the duration and magnitude of myelosuppression by either cytokine intervention (IL-1 and GM-CSF) and/or bone marrow transplantation (BMT). This reduction in host peripheral white blood cell (pWBC), thrombocyte and marrow colony forming unit (CFU) toxicity permitted a 25-50 percent increase in the maximal tolerated dose (MTD) of 131I-labeled and 90Y-labeled intact antibody and F(ab')2 fragments. The escalation in dose resulted in improved therapeutic outcome in both a subcutaneous bulky tumor xenograft model and in an intrapulmonary micrometastasis model. Evidence for RAIT-induced secondary toxicity stems from the inability to further dose escalate radioantibody beyond the level feasible with bolus dosing of cytokines, when using one of the following four approaches that is more efficacious at ameliorating RAIT-induced myelosuppression: 1) continuous infusion instead of bolus administration of cytokines, 2) cytokine intervention and second antibody (SA) administration, 3) cytokine intervention and BMT and 4) combined use of IL-l/GM-CSF and IL-7 together. Each of these four approaches results in pWBC and thrombocyte counts, spleen weight and marrow and spleen CFUs that remain within normal limits after administration of radio-iodinated and yttrium-labeled intact antibody and F(ab')2 fragments. In addition, preliminary clinical chemistry results suggests that changes in liver and kidney function occur in response to dose intensified RAIT. The goal of this renewal application is to ascertain the magnitude and duration of secondary end organ toxicity at the """"""""new MTD"""""""" following cytokine and/or BMT intervention and to then develop approaches that either affect radiation induced damage, e.g. new cytokines, antioxidant agents/free-radical scavengers, nutritional support, vascular agents, or alter distribution of radioantibody, e.g. renal reabsorption blocking agents, to overcome this toxicity as well. Only methods appropriate for the toxicity induced by a particular nuclide will be evaluated, e.g. if no GI toxicity results from a radiometal, then nutritional methods to curb GI toxicity will not be studied. It will then be determined whether the tolerated radioantibody dose can be further increased and whether control of tumor growth in both bulky and micrometastatic disease can be better controlled.
