SYSTEMIC T CELL IMMUNOTHERAPY OF MALIGNANT GLIOMAS

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Malignant brain tumors such as glioblastoma multiforme and anaplastic astrocytoma usually have a fatal outcome in spite of advances in diagnostic and treatment procedures. Enthusiasm to utilize immunotherapeutic approached for treatment of brain tumors was dampened by the concept of ~immune privilege~ of the central nervous system (CNS). However, recent data suggest that the CNS may not be an immunologically privileged site, albeit its distinct anatomical and physiological features. The CNS has the capacity to regulate immune responses by allowing a restricted entry of immune cells and providing a microenvironment that is conducive to the activation of effector cells. In animal experiments, tumors established in the brain are reactive to the systemically transferred immun T lymphocytes, resulting in tumor regression in an immunologically specific manner. Principles and methodology defined in animal studies have been extrapolated to develop a novel treatment for humans with high-grade gliomas. Patients will be immunized with irradiated autologous tumor cells along with GM-CSF as an adjuvant to boost the immune response. Draining lymph nodes resected surgically 7 days later will be activated in vitro with a bacterial superantigen, SEA followed by anti-CD3. A large number of such activated cells will be infused intravenously to the patient for adoptive T-cell immunotherapy. In this research-driven clinical trial, immunological and physiological properties of the activated T cells will be analyzed in detail. Toxicity, immunological reactivities and tumor responses of treated patients will be evaluated. It is hoped that this study will provide information for a better understanding of host-tumor interactions and for improving procedures for the generation of potent therapeutically effective T cells. The specific aims in this proposal are: 1) to assess the in vivo immunological reactivity of patients undergoing adoptive immunotherapy; 2) to elucidate mechanisms of antigen presentation and the adjuvant activity of GM-CSF; 3) to seek correlations between in vitro reactivities of lymph node T cells and their antitumor efficacy; and 4) to characterize adhesion/integrin molecules that are important in T cell activation as well as homing to the tumor site.