USE OF MURINE MODELS OF CYTOKINE-SECRETING TUMOR VACCINES TO STUDY FEASIBILITY AND TOXICITY ISSUES CRITICAL TO DESIGNING CLINICAL-TRIALS

In preclinical models, tumor cells genetically altered to secrete cyto kines or express costimulatory molecules can generate systemic antitum or immunity. In some studies, these tumor vaccines have been shown to eradicate micrometastases. These results have lead to the initiation o f numerous Phase I clinical trials employing either genetically modifi ed autologous or allogeneic tumor vaccines, We address a number of fea sibility and toxicity issues critical to the design of these immunothe rapy trials, using the B16 melanoma vaccine model. First, we demonstra ted the efficacy of freeze/thawed vaccine cells, a process required fo r conducting clinical trials with large numbers of vaccine cells, Seco nd, we performed pharmacokinetic studies and showed peak levels of gra nulocyte-macrophage colony-stimulating factor (GM-CSF) that are far be low levels expected to result in significant side effects in patients. Third, we performed autoimmune toxicity studies using the RENCA renal and B16 melanoma tumor vaccines and failed to demonstrate evidence of significant histologic or functional abnormalities. Overall, these no vel studies address important issues that should be considered in the design of clinical trials evaluating genetically modified tumor vaccin es.