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Jing Zeng,
Alfred P See, Jillian Phallen,
Christopher M Jackson,
Zineb Belcaid,
Jacob Ruzevick,
Nicholas Durham,
Christian Meyer,
Timothy J Harris,
Emilia Albesiano, [......],
Eric Ford,
John Wong,
Hans-Joerg Hammers,
Dimitris Mathios,
Betty Tyler,
Henry Brem,
Phuoc T Tran,
Drew Pardoll,
Charles G Drake,
Michael Lim
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ABSTRACT: PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. METHODS AND MATERIALS: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. RESULTS: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. CONCLUSIONS: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.
International journal of radiation oncology, biology, physics 02/2013; · 4.59 Impact Factor
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Alfred P See,
James E Han, Jillian Phallen,
Zev Binder,
Gary Gallia,
Fan Pan,
Dilini Jinasena,
Christopher Jackson,
Zineb Belcaid,
Sung Jin Jeong,
Chelsea Gottschalk,
Jing Zeng,
Jacob Ruzevick,
Sarah Nicholas,
Young Kim,
Emilia Albesiano,
Drew M Pardoll,
Michael Lim
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ABSTRACT: Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.
Journal of Neuro-Oncology 10/2012; · 3.21 Impact Factor
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ABSTRACT: Immunotherapy is a potential new therapeutic option in patients with high-grade gliomas (HGGs). Phase I/II trials have assessed the efficacy of increasing immune activity using vaccines made from lymphokine-activated killer cells, cytotoxic T cells, autologous tumor cells, or dendritic cells. Studies to decrease tumor immunoresistance have focused on cytokine modulation of known immunosuppressive factors in the tumor microenvironment. Several early studies have reported a survival benefit using different forms of immunotherapy. This article discusses past clinical trials using immunotherapy in HGGs, their efficacy, limits, and biologic and clinical design challenges that must be overcome to advance immunotherapy for patients with HGGs.
Neurosurgery clinics of North America 07/2012; 23(3):459-70. · 1.73 Impact Factor
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Jing Zeng,
Alfred P See,
Khaled Aziz,
Saravanan Thiyagarajan,
Tarek Salih,
Rajendra P Gajula,
Michael Armour, Jillian Phallen,
Stephanie Terezakis,
Lawrence Kleinberg,
Kristen Redmond,
Russell K Hales,
Roberto Salvatori,
Alfredo Quinones-Hinojosa,
Phuoc T Tran,
Michael Lim
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ABSTRACT: Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p < 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT-mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies.
Cancer biology & therapy 10/2011; 12(7):657-63. · 2.64 Impact Factor
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ABSTRACT: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment.
Clinical and Developmental Immunology 01/2011; 2011:732413. · 1.84 Impact Factor
