Cancer-Related Defects of the Immune System
Principal Investigator: Christopher Wheeler, PhD
T Cells and Glioma Malignancy
Enhancing Immune Cell Potency to Improve Brain Tumor Vaccine Therapy
The Immunology Research Program at the Cedars-Sinai Department of Neurosurgery is focused on determining how to best harness our body's natural defense systems to improve treatment of age-related brain disorders, including brain tumors. Researchers have developed a customized vaccine treatment against a patient's brain tumor that boosts natural immune defenses against the tumor. Recent results suggest that this vaccine both boosts natural "anti-tumor" responses, and prolongs patient survival (i.e. Phase II clinical trial). The Cedars-Sinai team is now working to find out which immune cells and molecules carry the vaccine's benefit. Previous work indicated that a type of newly produced immune cell that is rare in older individuals but plentiful in younger individuals; was dominating immune responses against brain tumors (gliomas) - both with and without vaccine treatment. Certain sugars that are attached to immune receptors on these particular immune cells can be removed using molecular scissors (enzymes) in order to increase their tumor-fighting responsiveness. The aim is to use this tool to further improve the effectiveness of this cancer vaccine.
Targeting Tumor Stem and Invasion Genes to Improve Brain Tumor Immunotherapy
Gliomas behave differently from other tumors, invading and harming normal brain rather than distant tissues. The Immunology Program found that natural immune activity decreased brain invasiveness in gliomas (even without vaccine treatment). This change in glioma behavior was accompanied by reduced expression of a cancer-causing gene called epidermal growth factor receptor (EGFR), and increased expression of genes expressed in stem cells. Researchers are working to find out if treatments (drugs) that decrease either EGFR or stem cell gene expression without increasing tumor-fighting immunity can reduce brain tumor invasiveness and malignancy. Such knowledge could improve vaccine treatment by combining it with complementary drugs, or make at least some of the benefits of vaccine treatment applicable to more patients.
Age-related Immune Cells in Brain Cancer and Neurodegenerative Disorders
Promoting Protective Immunity in Neurodegeneration
It has long been thought that immune cells enter the brain in large numbers only in disease situations. The Immunology Research Program recently uncovered evidence that a group of immune cells resides in brains of healthy young individuals and that these immune cells decrease in number with age. In general, these immune cells could conceivably protect against age-related brain disorders, and their absence might set the stage to promote brain disease. In this context, immune cell presence improved the outcome of an experimental Parkinson's disease (PD)-like disorder, and protected normal mice from the detrimental effects of brain inflammation, an implication in many neurodegenerative disorders such as PD and Alzheimer's disease (AD). It is anticipated that the knowledge gained from pursuing this line of investigation will help treat these two most common age-related diseases.
Jouanneau, E.*, Veiga, L*., Black, K.L., Gragg, A., Zandian, M., Zhai, Y., Zhang, X-x., Morris-Irvin, D., Wheeler, C.J. Recent thymic emigrant CD8+ T cells and surface under-sialylation mediate strong reactivity to intracranial glioma antigen and autologous neural progenitors. (*co-first authors) Soc. for Neuroscience Annual Mtg, San Diego, CA, Nov 3-7, 2007.
Morris-Irvin, D., Jouanneau, E., Duvall, G., Zhai, Y., Zhang, X-x., Sarayba, D., Sekseyan, A., Black, K.L., Wheeler, C.J. Vaccination uniquely elicits stem-like phenotype, function, and increased dependence on hedgehog signaling in gliomas. Soc. for Neuroscience Annual Mtg, San Diego, CA, Nov 3-7, 2007.
Sarayba, D., Espinosa, A., Zhai, Y., Gragg, A., Wheeler, C.J., Black, K.L., Irvin, D. T lymphocytes confer neurobehavioral benefit in a 6-OHDA model of Parkinson's Disease. Soc. for Neuroscience Annual Mtg, San Diego, CA, Nov 3-7, 2007.
Wheeler, C. J., K. L. Black, G. Liu, M. Wagenberg, X.-x. Zhang, S. Pepkowitz, D. Goldfinger, H. Ng, D. Irvin, and J. S. Yu. (2008) Vaccination elicits correlated immune and clinical responses in patients with glioblastoma multiforme. Cancer Res 68 (14): 5955-64, 2008.
Zhang, X.-x., Black, K.L., Ong, J.M., Bogler, O., Zhai, Y., and Wheeler, C.J. (2005) T cell activity in glioma chemoresponsiveness and genetics. Gene Ther Mol Biol 9:401-416.
Liu, G., Akasaki, Y., Khong, H.T., Wheeler, C.J., Das, A., Black, K.L., and Yu, J.S. (2005) Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy. Oncogene 24:5226-34.
Wheeler, C.J., and Black, K. (2005) Dendritic Cell Vaccines and Obstacles to Beneficial Immunity in Glioma Patients. Current Opinion Mol Ther 7:35-47.
Wheeler, C.J., Das, A., Liu, G., Yu, J.S., and Black, K. (2004) Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 10:5316-5326. (selected as featured article)
Yu, J.S., Liu, G., Ying, H., Yong, W.H., Black, K.L., and Wheeler, C.J. (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits specific cytotoxic T cells in patients with malignant glioma. Cancer Res 64:4973-4979.
Liu, G., Ying, H., Zeng, G., Wheeler, C.J., Black, K.L., and Yu, J.S. (2004) HER-2, gp100 and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980-4986.
Prins, R.M., Incardona, F., Lau, R., Lee, P.K., Black, K.L., Claus, S., Zhang, W., and Wheeler, C.J. (2004) Characterization of defective CD4-8- T cells in murine tumors generated independent of antigen specificity. J Immunol 172, 1602-1611.
Wheeler, C.J., Black, K.L., Liu, G., Gutierrez, M., Ying, H., Yu, J.S., Zhang, W., and Lee, P.K. (2003) Thymic CD8+ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J Immunol 171, 4927-4933.
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