The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. Severaltrials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines. However the generalapplicability of effective glioma immunotherapy has yet to be clearly documented. Vaccine therapiesdesigned to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells andcytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergoanergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be renderedineffective by proteins that confer resistance to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated killing. B7-Homologue 1 (B7-H1), also known as programmed death ligand 1 (PD-L1), is arecently discovered cell surface protein that inhibits anti-tumor immunity by inducing T-cell apoptosis,impairing cytokine production, and diminishing the cytotoxicity of activated T-cells. FADD-containing inhibitorof caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. Webelieve that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of gliomaimmunotherapy. In our preliminary results, we show that B7-H1 and FLIPS are positively regulated by thePI(3)K/Akt/mTOR pathway, and that glioma cells with this pathway activated are immunoresistant. Inaddition we show that an autologous patient-specific vaccine containing glioma-derived heat shock proteinpeptide complex-96 (HSPPC-96) appears to be safe, while evoking a tumor specific T-cell response and anincrease in circulating NK cells. To translate our experimental findings into the clinic, we will test thehypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) andadaptive (T-cell) anti-glioma immune responses. In order to test our hypothesis in a clinically relevant in vitrosystem, aims #1 and #2 utilize glioma cells directly from glioblastoma multiforme (GBM) patients andpassaged as xenografts, prior to culturing to assess the impact of PI(3)K/Akt/mTOR pathway on resistanceto NK and T cell killing.
In aim #3 we will study gliomas taken directly from patients to assess therelationship between PI(3)K/Akt/mTOR pathway activation and T-cell infiltration, and in aim #4 we will testour hypothesis within the context of an ongoing HSPPC-96 phase l/ll vaccine trial for glioma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA097257-06
Application #
7253809
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
6
Fiscal Year
2007
Total Cost
$296,969
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Luks, Tracy L; McKnight, Tracy Richmond; Jalbert, Llewellyn E et al. (2018) Relationship of In Vivo MR Parameters to Histopathological and Molecular Characteristics of Newly Diagnosed, Nonenhancing Lower-Grade Gliomas. Transl Oncol 11:941-949
Viswanath, Pavithra; Radoul, Marina; Izquierdo-Garcia, Jose Luis et al. (2018) 2-Hydroxyglutarate-Mediated Autophagy of the Endoplasmic Reticulum Leads to an Unusual Downregulation of Phospholipid Biosynthesis in Mutant IDH1 Gliomas. Cancer Res 78:2290-2304
An, Zhenyi; Knobbe-Thomsen, Christiane B; Wan, Xiaohua et al. (2018) EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma. Cancer Res 78:6785-6794
Mancini, Andrew; Xavier-Magalhães, Ana; Woods, Wendy S et al. (2018) Disruption of the ?1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell 34:513-528.e8
Disney-Hogg, Linden; Sud, Amit; Law, Philip J et al. (2018) Influence of obesity-related risk factors in the aetiology of glioma. Br J Cancer 118:1020-1027
Goode, Benjamin; Mondal, Gourish; Hyun, Michael et al. (2018) A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 9:810
Takahashi, Hannah; Cornish, Alex J; Sud, Amit et al. (2018) Mendelian randomisation study of the relationship between vitamin D and risk of glioma. Sci Rep 8:2339
Amirian, E Susan; Ostrom, Quinn T; Armstrong, Georgina N et al. (2018) Aspirin, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-Analysis. Cancer Epidemiol Biomarkers Prev :
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Disney-Hogg, Linden; Cornish, Alex J; Sud, Amit et al. (2018) Impact of atopy on risk of glioma: a Mendelian randomisation study. BMC Med 16:42

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