TUMOR-ANTIGENS IN ASTROCYTIC GLIOMAS

Gliomas affect 15,000 to 17,000 Americans every year and carry a disma l prognosis. The potential of immunologically mediated diagnosis and t herapy, although greatly enhanced since the advent of monoclonal antib odies, has not been fully realized due to significant problems, most e specially the challenge of identifying antigenic molecules specific to glial tumors. Other problematic issues include antigen-associated fac tors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent deli very, typically variable tumor perfusion and unfavorable diffusional f orces in tumor microenvironment. An understanding of these problems ca lled for the delineation of operationally specific antigens (tumor-ass ociated antigens not expressed by the normal central nervous system) c ombined with the use of compartmental therapeutic approaches to increa se the specificity of therapy. Numerous antigens have been identified and are classified as extracellular/ matrix-associated, membrane-assoc iated, and intracellular antigens. Nevertheless, only a few have been demonstrated to be of significant therapeutic and diagnostic utility. These few include the extracellular matrix-associated antigens tenasci n and GP 240, defined by the monoclonal antibodies 81C6 and Mel-14, bo th of which are now in Phase I clinical trials, and membrane-associate d ganglioside molecules, primarily 3',6'-isoLD1, defined by the antibo dy DMAb-22. Recent identification of the overexpression of a deletion variant of the epidermal growth factor receptor (EGFRvIII) in up to 50 % of the more malignant glial tumors and the subsequent creation of mo noclonal antibodies that are specific to this molecule and do not reco gnize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma immunoconjugates. In addition, the t umor-specific nature of EGFRvIII combined with improved knowledge of i mmune mechanisms, especially in the context of the central nervous sys tem, will facilitate the design of highly selective cell-mediated ther apeutic approaches with a view toward obtaining tumor-specific immunit y. (C) 1995 Wiley-Liss, Inc.