Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer. Even after surgical resection, irradiation and chemotherapy, the median survival for patients with GBM remains at only 14.6 months, with 26% of patients alive after 2 years. The potent immunosuppression induced by GBM is one of the primary obstacles to finding effective immunotherapies. This immunosuppression is associated with a significant accumulation of regulatory T cells (CD4+CD25+FoxP3+, Tregs) within the tumor microenvironment and is considered to be one of the primary obstacles inhibiting the tumor rejection functions of CD8+ cytotoxic T cells. It is therefore important that future immunotherapies simultaneously arm effector CD8+ cytotoxic T cells, while at the same time inhibiting immunosuppressive mechanisms. Building on our expertise in brain tumor immunology, we now propose to elucidate the mechanisms involved in GBM immunosuppression and to investigate the function of a novel immunomodulatory agent in the context of a phase I/II human clinical trial. Cumulatively, our studies will comprehensively characterize the immunosuppressive microenvironment of gliomas and test the clinical efficacy of a new drug capable of reversing GBM mediated immune tolerance.

Public Health Relevance

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central nervous system (CNS). Although immunotherapy represents an attractive approach for this cancer, local immunosuppression associated with GBM microenvironment represents a major problem. This proposal seeks to evaluate the role of indoleamine 2,3-dioxygenase (IDO), a key enzyme in tryptophan metabolism, in GBM immunosuppression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS093903-03
Application #
9113102
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fountain, Jane W
Project Start
2015-08-01
Project End
2020-04-30
Budget Start
2017-09-15
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Chang, Alan L; Miska, Jason; Wainwright, Derek A et al. (2016) CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer Res 76:5671-5682