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01-06-2020 | Glioblastoma | Laboratory Investigation

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

Authors: Dominic Maggio, Winson S. Ho, Rebecca Breese, Stuart Walbridge, Herui Wang, Jing Cui, John D. Heiss, Mark R. Gilbert, John S. Kovach, Rongze O. Lu, Zhengping Zhuang

Published in: Journal of Neuro-Oncology | Issue 2/2020

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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Title: Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma
Authors: Dominic Maggio
Winson S. Ho
Rebecca Breese
Stuart Walbridge
Herui Wang
Jing Cui
John D. Heiss
Mark R. Gilbert
John S. Kovach
Rongze O. Lu
Zhengping Zhuang
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Journal of Neuro-Oncology / Issue 2/2020
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-020-03517-5

At a glance: The STEP trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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