Dominic Maggio1, Winson S Ho2,3, Rebecca Breese1, Stuart Walbridge1, Herui Wang4, Jing Cui4, John D Heiss1, Mark R Gilbert4, John S Kovach5, Rongze O Lu6,7, Zhengping Zhuang8,9. 1. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. 2. Department of Neurosurgery, Dell Medical School, University of Texas at Austin, Austin, TX, 78701, USA. winson.ho@austin.utexas.edu. 3. University of Texas at Austin, 1601 Trinity St, Bldg. B HDB 3.214, Austin, TX, 78701, USA. winson.ho@austin.utexas.edu. 4. Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. 5. Lixte Biotechnology Holdings, Inc., East Setauket, NY, 11733, USA. 6. Department of Neurosurgery, Dell Medical School, University of Texas at Austin, Austin, TX, 78701, USA. Rongze.lu@austin.utexas.edu. 7. University of Texas at Austin, 1601 Trinity St, Bldg. B HDB 3.216, Austin, TX, 78701, USA. Rongze.lu@austin.utexas.edu. 8. Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. zhengping.zhuang@nih.gov. 9. National Institutes of Health, BLDG 35, Rm 2B203, Bethesda, MD, 20892, USA. zhengping.zhuang@nih.gov.
Abstract
PURPOSE: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management. Emerging evidence suggests that protein phosphatase 2A (PP2A) plays a critical role in the signal transduction pathways of both adaptive and innate immune cells and that inhibition of PP2A could enhance cancer immunity. We investigated the use of a PP2A inhibitor, LB-100, to enhance antitumor efficacy of PD1 blockade in a syngeneic glioma model. METHODS: C57BL/6 mice were implanted with murine glioma cell line GL261-luc or GL261-WT and randomized into 4 treatment arms: (i) control, (ii) LB-100, (iii) PD1 blockade and (iv) combination. Survival was assessed and detailed profiling of tumor infiltrating leukocytes was performed. RESULTS: Dual PP2A and PD1 blockade significantly improved survival compared with monotherapy alone. Combination therapy resulted in complete regression of tumors in about 25% of mice. This effect was dependent on CD4 and CD8 T cells and cured mice established antigen-specific secondary protective immunity. Analysis of tumor lymphocytes demonstrated enhanced CD8 infiltration and effector function. CONCLUSION: This is the first preclinical investigation of the effect of combining PP2A inhibition with PD1 blockade for GBM. This novel combination provided effective tumor immunotherapy and long-term survival in our animal GBM model.
PURPOSE:Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management. Emerging evidence suggests that protein phosphatase 2A (PP2A) plays a critical role in the signal transduction pathways of both adaptive and innate immune cells and that inhibition of PP2A could enhance cancer immunity. We investigated the use of a PP2A inhibitor, LB-100, to enhance antitumor efficacy of PD1 blockade in a syngeneic glioma model. METHODS: C57BL/6 mice were implanted with murineglioma cell line GL261-luc or GL261-WT and randomized into 4 treatment arms: (i) control, (ii) LB-100, (iii) PD1 blockade and (iv) combination. Survival was assessed and detailed profiling of tumor infiltrating leukocytes was performed. RESULTS: Dual PP2A and PD1 blockade significantly improved survival compared with monotherapy alone. Combination therapy resulted in complete regression of tumors in about 25% of mice. This effect was dependent on CD4 and CD8 T cells and cured mice established antigen-specific secondary protective immunity. Analysis of tumor lymphocytes demonstrated enhanced CD8 infiltration and effector function. CONCLUSION: This is the first preclinical investigation of the effect of combining PP2A inhibition with PD1 blockade for GBM. This novel combination provided effective tumor immunotherapy and long-term survival in our animal GBM model.
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Authors: Winson S Ho; Michael J Feldman; Dragan Maric; Lauren Amable; Matthew D Hall; Gerald M Feldman; Abhik Ray-Chaudhury; Martin J Lizak; Juan-Carlos Vera; R Aaron Robison; Zhengping Zhuang; John D Heiss Journal: Oncotarget Date: 2016-03-15