Malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) are the most frequent primary brain tumors in adults and account for about 2 percent of all cancers. It is currently incurable, inevitably fatal, and inflicts an enormous social and economic impact, often striking patients during the prime of their lives. This sobering fact underscores the need to rethink standard approaches to treating brain cancer and to base therapeutic strategies on advances in our understanding of basic cancer biology and tumor immunology. Although a recent renaissance in cancer vaccine research has produced a plethora of approaches designed to elicit immune responses against extra-cranial tumors, there is a paucity of rigorous clinical evaluations of immunotherapeutic treatments for intra-cranial brain tumors. This is due primarily to gaps in our existing knowledge of the unique immunological milieu of the central nervous system (CNS), which have limited conclusive hypotheses about whether brain tumor immunotherapy is actually feasible, safe, or clinically relevant. Therefore, the broad, long-term objectives of this research are: i) to develop and optimize immunotherapy approaches for the clinical treatment of intracranial brain tumors; and ii) to gain a better understanding of the anti-tumor immune responses generated within the traditionally """"""""immune privileged"""""""" CNS. In order to achieve these objectives, this project initiates a Phase I study of dendritic cell (DC) immunotherapy for patients with malignant gliomas. Dendritic cells, antigen-presenting cells specialized to elicit cellular immunity, have been used in pilot clinical trials for patients with non-CNS cancers.
The specific aims of our project are: 1) to determine the feasibility, safety and toxicity of intradermal injections of autologous peptide-pulsed dendritic cells in patients with CNS gliomas; 2) to monitor tumor progression and cellular/humoral immune responses in brain tumor patients injected with antigen-pulsed dendritic cells and compare them with those of historical controls; and 3) to evaluate the nature of immune infiltrates and cytokine profiles in brain tumor specimens prior to treatment (at initial surgical resection) and following DC vaccination (at subsequent surgical resection for recurrence or autopsy). Correlation of the clinical and immunological response data in these patients will hopefully validate mechanistic hypotheses that systemic immune responses can translate to relevant immune responses within the CNS, which in turn may result in clinical benefit for brain tumor patients. The results of this research will help to determine the pertinent clinical and immunological endpoint measures that can meaningfully guide further clinical development of brain tumor immunotherapies.
