Malignant gliomas are responsible for significant morbidity and mortality, with a median survival of less than two years. Despite advances in neurosurgery, radiation, and chemotherapy, the prognosis of patients with these fatal brain tumors remains grim. Among the new treatments currently being investigated for malignant cancers, none is as theoretically appealing as immunotherapy because it offers the potential for high tumor-specific toxicity. However, despite some successful trials of immunotherapy against certain extracranial cancers, studies of immune responses against intracranial tumors have not yielded promising results. One explanation for this is that early attempts at brain tumor immunotherapy relied upon crude tumor cell preparations or general immune stimulants, which lacked specificity. Ultimately, the success of cancer immunotherapy as a standardized treatment for malignant brain tumors depends upon the ability of the proposed vaccine to stimulate a specific anti-tumor (and not anti-brain) immune response. Theoretically, such a response can optimally be achieved with the identification of tumor-specific gene products (antigens) that can be selectively presented to the host immune system. Not until the identification of operational glioma-specific antigens (present in tumor tissue but not in normal brain) will the theoretical promise of brain tumor immunotherapy be fully realized. Therefore, the challenge of identifying antigenic gene products specific to glial tumors is a crucial first objective in selecting appropriate targets for immune attack. To achieve this goal, this proposal aims to: 1) identify putative glioma-specific genes using established and novel subtractive cloning approaches; 2) characterize these genes using modern molecular methods coupled with high-throughput gene arraying technology; and 3) translate candidate glioma-specific gene products found in vitro into potential therapeutic targets for brain tumor immunotherapy in animal models in vivo by using professional antigen-presenting dendritic cells or the bacterial vector Listeria monocytogenes to deliver antigens to the cellular arm of the host immune response. Hopefully, these research aims and methods will not only provide some new insight into understanding the molecular biology and pathogenesis of malignant brain tumors, but also fill some of the gaps in our existing knowledge of neuro-immunology and immune-based therapies for neurological cancers.
