A crucial question in the study of tumor neuro-immunology concerns the capacity of the central nervous system to initiate and execute an immune response. In a 100 percent fatal rat malignant glioma model, genetically-modified tumors secreting INF-'intracerebrally generate an immune response resulting in a substantial increase in survival time, tumor rejection, and specific systemic immunity. IL-2 secreted by genetically-modified tumors does not change the biologic behavior of transfected gliomas. INF-' induces elevated expression of major histocompatibility complex class I and class II molecules in microglia throughout the brain and invokes enhanced tumor infiltration by CD4, CD8, and NK cells. These findings demonstrate the successful immunization against a central nervous system tumor by direct priming in the brain with a live growth-competent tumor vaccine. The broad and long term objectives of this research are to clarify the basic principles responsible for the initiation of an immune response after priming in the brain, and to devise novel immunotherapeutic strategies for the treatment of patients with malignant brain tumors. The specific research proposed in this application is intended to examine the capacity of microglia to function as competent antigen presenting cells to tumor specific antigens, and the role of major histocompatibility antigen class I/II molecules and CD4/CD8 cells in the initiation of such an immune response. The importance and health relevance of this research are exemplified by our therapeutic results in animals showing that, in a universally fatal brain tumor model, 95 percent of the rats implanted intracerebrally with INF-'-secreting tumors survive substantially longer than controls, and 43 percent reject the tumor and develop protective systemic immunity. The results of the proposed research will provide conclusive evidence whether microglia are responsible for presenting CNS-derived tumor antigens, and are crucial for designing future immunotherapeutic strategies for the treatment of patients with either primary or metastatic brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA078825-01
Application #
2688050
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Mccarthy, Susan A
Project Start
1998-07-16
Project End
2003-06-30
Budget Start
1998-07-16
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Fathallah-Shaykh, Hassan M (2002) Darts in the dark cure animal, but not human, brain tumors. Arch Neurol 59:721-4
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Fathallah-Shaykh, H M (2000) Fiction, reality, and molecular neurology. Arch Neurol 57:63-4