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Published on: February 16, 2015
Inhibition of PP2A with LB-100 Enhances Efficacy of CAR-T Cell Therapy Against Glioblastoma
Jing Cui1, Herui Wang1, Rogelio Medina2,3
1Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, 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.
Insights
Combining LB-100 with carbonic anhydrase IX (CAIX)-targeted CAR-T cell therapy enhances glioblastoma treatment. This combination boosts T cell activity, offering a synergistic approach for solid tumors.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy shows promise for glioblastoma.
- Targeting carbonic anhydrase IX (CAIX) with CAR-T cells is effective in preclinical models.
- CAR-T cell activation is often suboptimal within the tumor microenvironment.
Purpose of the Study:
- To investigate the synergistic anti-tumor effect of combining LB-100 with anti-CAIX CAR-T cell therapy.
- To evaluate if LB-100 enhances the efficacy of anti-CAIX CAR-T cell treatment.
- To explore the potential of this combination therapy for solid tumors.
Main Methods:
- In vitro and in vivo studies were conducted using a murine glioblastoma model.
- LB-100, a protein phosphatase 2A (PP2A) inhibitor, was used in combination with anti-CAIX CAR-T cells.
- T cell activation, cytotoxic activity, and anti-tumor effects were assessed.
Main Results:
- LB-100 significantly enhanced the efficacy of anti-CAIX CAR-T cell therapy.
- The combination treatment demonstrated improved anti-tumor activity in vitro and in vivo.
- LB-100 was shown to augment the cytotoxic activity of anti-CAIX CAR-T cells.
Conclusions:
- Combination therapy with LB-100 and anti-CAIX CAR-T cells exhibits synergistic anti-tumor effects.
- LB-100 enhances CAR-T cell function, overcoming limitations in the tumor microenvironment.
- This combined approach holds therapeutic potential for glioblastoma and other solid tumors.
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