Inhibition of PP2A with LB-100 Enhances Efficacy of CAR-T Cell Therapy Against Glioblastoma

Jing Cui; Herui Wang; Rogelio Medina; Qi Zhang; Chen Xu; Iris H Indig; Jingcheng Zhou; Qi Song; Pauline Dmitriev; Mitchell Y Sun; Liemei Guo; Yang Wang; Jared S Rosenblum; John S Kovach; Mark R Gilbert; Zhengping Zhuang

doi:10.3390/cancers12010139

Inhibition of PP2A with LB-100 Enhances Efficacy of CAR-T Cell Therapy Against Glioblastoma

Cancers (Basel). 2020 Jan 6;12(1):139. doi: 10.3390/cancers12010139.

Authors

Jing Cui¹, Herui Wang¹, Rogelio Medina^{2

3}, Qi Zhang¹, Chen Xu¹, Iris H Indig¹, Jingcheng Zhou¹, Qi Song¹, Pauline Dmitriev¹, Mitchell Y Sun², Liemei Guo², Yang Wang¹, Jared S Rosenblum¹, John S Kovach⁴, Mark R Gilbert¹, Zhengping Zhuang^{1

2}

Affiliations

¹ Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁴ Lixte Biotechnology Holdings, Inc., East Setauket, NY 11733, USA.

Abstract

Chimeric antigen receptor (CAR)-engineered T cells represent a promising modality for treating glioblastoma. Recently, we demonstrated that CAR-T cells targeting carbonic anhydrase IX (CAIX), a protein involved in HIF-1a hypoxic signaling, is a promising CAR-T cell target in an intracranial murine glioblastoma model. Anti-CAIX CAR-T cell therapy is limited by its suboptimal activation within the tumor microenvironment. LB-100, a small molecular inhibitor of protein phosphatase 2A (PP2A), has been shown to enhance T cell anti-tumor activity through activation of the mTOR signaling pathway. Herein, we investigated if a treatment strategy consisting of a combination of LB-100 and anti-CAIX CAR-T cell therapy produced a synergistic anti-tumor effect. Our studies demonstrate that LB-100 enhanced anti-CAIX CAR-T cell treatment efficacy in vitro and in vivo. Our findings demonstrate the role of LB-100 in augmenting the cytotoxic activity of anti-CAIX CAR-T cells and underscore the synergistic therapeutic potential of applying combination LB-100 and CAR-T Cell therapy to other solid tumors.

Keywords: CAIX; CAR-T; LB-100; PP2A; glioblastoma.