This program project is a continuation of three interrelated project including experimental and clinical approaches to new techniques of diagnosis and therapy of human melanoma, pancreatic carcinoma, and glioblastoma. The melanoma studies include purification of selected human melanoma tumor associated antigens (TAA) in preparation for specific active immunotherapeutic trials. We will continue studies designed to test the immunogenicity of these TAA in subhuman primates and man. A phase I clinical trial using two of the purified TAA in a specific active immunotherapy protocol is proposed. We will produce second generation monoclonal antibodies (MoAbs) using the purified TAA preparations as the immunogens. During the last grant period we successfully generated and partially characterized human cytotoxic T-cells reactive with melanoma tumor antigens. We now propose cloning and expansion of these cytotoxic T-cell lines and will assess the functional properties and specificity of the expanded clones in preparation for phase I human trials. We will evaluate the effect of recombinant IL-2 on marrow reconstitution and will complete studies of both cell phenotype and function as an a prelude to combining adoptive immunotherapy with high chemotherapy and autologous bone marrow support. We have produced and characterized and number of murine MoAbs reactive with human pancreatic adenocarcinomas. We now proposed to continue these studies directed toward isolation and purification of selected TAA of pancreatic adenocarcinomas. Our preliminary results have suggested that we will be able to produce and characterize cytotoxic T-cells that are reactive with defined pancreatic TAA. We proposed a Phase I passive immunotherapeutic trial in patients with pancreatic adenocarcinoma. During the last grant period we also were successful in developing and characterizing a panel of MoAbs antibodies reactive with brain tumor cells. We propose pharmacokinetic and biodistribution studies in non-human primates using selected MoAbs that are reactive with both human gliomas and melanomas. We will conduct a series of phase I and phase II imaging studies in patients with primary glioblastoma and melanomas metastatic to brain in an effort to determine which MoAb or combinations of MoAbs are most effective for imaging brain tumors. We also will evaluate the radioimmunotherapeutic potential of individual and combinations of MoAbs reactive with human gliomas and metastatic melanomas to brain in a phase II clinical trial.
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