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Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma

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Journal of Neuro-Oncology Aims and scope Submit manuscript

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.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The research was supported by the Intramural Research Program of the NINDS and NCI of the National Institutes of Health.

Author information

Author notes

  1. Dominic Maggio, Winson S. Ho and Rebecca Breese contributed equally to this work.

Authors and Affiliations

  1. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Dominic Maggio, Rebecca Breese, Stuart Walbridge & John D. Heiss

  2. Department of Neurosurgery, Dell Medical School, University of Texas at Austin, Austin, TX, 78701, USA

    Winson S. Ho & Rongze O. Lu

  3. Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Herui Wang, Jing Cui, Mark R. Gilbert & Zhengping Zhuang

  4. Lixte Biotechnology Holdings, Inc., East Setauket, NY, 11733, USA

    John S. Kovach

  5. University of Texas at Austin, 1601 Trinity St, Bldg. B HDB 3.214, Austin, TX, 78701, USA

    Winson S. Ho

  6. University of Texas at Austin, 1601 Trinity St, Bldg. B HDB 3.216, Austin, TX, 78701, USA

    Rongze O. Lu

  7. National Institutes of Health, BLDG 35, Rm 2B203, Bethesda, MD, 20892, USA

    Zhengping Zhuang

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  1. Dominic Maggio
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Contributions

Conception and design—WH, RL, ZZ. Development of methodology—WH, RL, ZZ. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.)—RB, DM, WH, SW, HW, JC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis)—RB, DM, WH, RL, ZZ, JH, MG. Writing, review, and/or revision of the manuscript—WH, RB, ZZ, JH, MG, JK. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases)—WH, DM, ZZ, JH.

Corresponding authors

Correspondence to Winson S. Ho, Rongze O. Lu or Zhengping Zhuang.

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Conflict of interest

WH is a board member and has stock options for Lixte Biotechnology Holdings Inc. JK is a board member and own stocks for Lixte Biotechnology Holdings Inc. WH, HW, RL, JK, ZZ have pending patents related to this work. No potential conflicts of interest were disclosed by the other authors.

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Maggio, D., Ho, W.S., Breese, R. et al. Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma. J Neurooncol 148, 231–244 (2020). https://doi.org/10.1007/s11060-020-03517-5

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  • DOI: https://doi.org/10.1007/s11060-020-03517-5

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