John H. Sampson

Biological Principles of Brain Tumor Immunotherapy

The objective of this chapter is to discuss the biological principles that currently guide the design of immunotherapies (ITs) directed against central nervous system (CNS) tumors. Direct translation of systemic ITs currently in use to CNS tumors is limited by the heterogeneity of gliomas, immunosuppression mediated by cytokines elaborated by gliomas, and the possible induction, in the case of nonspecific ITs, of potentially lethal autoimmune reactions. In order to design rational ITs, a clear knowledge of immunological responses within the CNS is required. The basic tenet of “immunological privilege” is placed within the more proper context of immunological suppression. Emerging concepts, such as antigen (Ag) presentation within the CNS and the presence of CNS complement, are presented as well, because these areas represent new potential areas for therapeutic intervention. Discussion of application of this information, including manipulation of cytokines, adoptive IT, vaccination, and tumor-specific Ag approaches, is reserved for other chapters.

Cytokine-Based Gene Therapy for Brain Tumors

The purpose of this chapter is to review the application of gene therapy approaches, with an emphasis on the use of cytokine genes, to the induction of a cell-mediated immune response useful in the treatment of brain tumors. This chapter begins with a review of general issues specific to the immunologic environment of the central nervous system (CNS) and the immunotherapy of brain tumors, in order to place subsequent discussions in an enlightened context and to allow for critical appraisal of the data presented in the second part of this chapter. A thorough discussion of the animal models commonly used in experimental neuro-oncology is given special emphasis, because the misuse of such models may have a more profound influence on the results from gene-based experimental immunotherapy than it does in other areas of experimental neurooncology. Failure to evaluate the results of such experiments in the context of the appropriateness of the experimental model may produce misleading conclusions that could delay the rational development of efficacious immunotherapeutic strategies. In the second part of this chapter, the recent literature dealing with the use of cytokine gene transfer to induce or enhance a direct cytotoxic effect, or a cell-mediated immune response against brain tumors, is reviewed and evaluated. Finally, some of the questions that remain and the problems that need to be solved are introduced as a stimulant to further work in this area.