Gliomas affect 15,000 to 17,000 Americans every year and carry a dismal prognosis. The potential of immunologically mediated diagnosis and
therapy, although greatly enhanced since the advent of
monoclonal antibodies, has not been fully realized due to significant problems, most especially the challenge of identifying antigenic molecules specific to glial
tumors. Other problematic issues include
antigen-associated factors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent delivery, typically variable
tumor perfusion and unfavorable diffusional forces in tumor microenvironment. An understanding of these problems called for the delineation of operationally specific
antigens (tumor-associated
antigens not expressed by the normal central nervous system) combined with the use of compartmental therapeutic approaches to increase the specificity of
therapy. Numerous
antigens have been identified and are classified as extracellular/matrix-associated, membrane-associated, 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 tenascin and GP 240, defined by the
monoclonal antibodies 81C6 and Mel-14, both of which are now in Phase I clinical trials, and membrane-associated
ganglioside molecules, primarily 3', 6'-isoLD1, defined by the antibody 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
monoclonal antibodies that are specific to this molecule and do not recognize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma
immunoconjugates. In addition, the
tumor-specific nature of
EGFRvIII combined with improved knowledge of immune mechanisms, especially in the context of the central nervous system, will facilitate the design of highly selective cell-mediated therapeutic approaches with a view toward obtaining
tumor-specific immunity.