The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. Several trials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines. However the general applicability of effective glioma immunotherapy has yet to be clearly documented. Vaccine therapies designed to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells and cytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be rendered ineffective 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 a recently 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 inhibitor of caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. We believe that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of glioma immunotherapy. In our preliminary results, we show that B7-H1 and FLIPS are positively regulated by the PI(3)K/Akt/mTOR pathway, and that glioma cells with this pathway activated are immunoresistant. In addition we show that an autologous patient-specific vaccine containing glioma-derived heat shock protein peptide complex-96 (HSPPC-96) appears to be safe, while evoking a tumor specific T-cell response and an increase in circulating NK cells. To translate our experimental findings into the clinic, we will test the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) and adaptive (T-cell) anti-glioma immune responses. In order to test our hypothesis in a clinically relevant in vitro system, aims #1 and #2 utilize glioma cells directly from glioblastoma multiforme (GBM) patients and passaged as xenografts, prior to culturing to assess the impact of PI(3)K/Akt/mTOR pathway on resistance to NK and T cell killing.
In aim #3 we will study gliomas taken directly from patients to assess the relationship between PI(3)K/Akt/mTOR pathway activation and T-cell infiltration, and in aim #4 we will test our hypothesis within the context of an ongoing HSPPC-96 phase l/ll vaccine trial for glioma patients.
|Ostrom, Quinn T; Kinnersley, Ben; Armstrong, Georgina et al. (2018) Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age. Int J Cancer 143:2359-2366|
|Pekmezci, Melike; Stevers, Meredith; Phillips, Joanna J et al. (2018) Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta Neuropathol 135:485-488|
|Behr, Spencer C; Villanueva-Meyer, Javier E; Li, Yan et al. (2018) Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR. JCI Insight 3:|
|Taylor, Jennie W; Parikh, Mili; Phillips, Joanna J et al. (2018) Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma. J Neurooncol 140:477-483|
|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|
Showing the most recent 10 out of 362 publications