The purpose of this application is to support the development of Dr. Mark Jennings as an academic pediatric neurooncologist, with a clinical emphasis on the management of pediatric brain tumors, and a research emphasis on the immunobiology of pediatric brain tumors. The immunologic investigation proposed is a continuation of serologic analysis conducted by the candidate since July 1983. Murine monoclonal antibodies (MAB) are being generated against human Medulloblastomas, Neuroblastomas and Anaplastic Astrocytomas.
The specific aims are the identification of tumor-restricted and neuroglial differentiation antigens and the development of monoclonal antibody imaging and immunotherapy. Selected antibodies are to be developed for three areas of application. First is the construction of a schema of differentiation among primitive neuroectodermal tumors which would reflect neuroglial maturation steps. Second is the neuropathologic investigation of the cell surface antigens of primary central nervous system (CNS) tumors in order to develop a prognostically relevant classification. Thirdly, antibodies with sufficient specificity are to be evaluated for eventual development in clinical diagnostic imaging and therapy. The accomplishment of this requires: (1) the establishment of new medulloblastoma cell lines, collection and maintenance of existent neuroblastoma and astrocytoma lines, (2) hybridoma technology, (3) serologic, (4) immunohistochemical techniques to define the specificity of the antibodies produced, (5) biochemical methods to evaluate the nature of the antigens identified by the antibodies and (6) genetic analysis beginning with the chromosomal assignment through somatic cell genetic analysis. (7) Eventually MAB imaging and immunotherapy will be developed. In the case of therapy both cytotoxic antibodies and noncytotoxic antibodies conjugated with a toxin or radioisotope will be studied. This broad yet directed training is critical preparation for a career in academic medicine emphasizing clinical investigation in tumor immunology.
