Details

Autor(en) / Beteiligte

• Cui, Jing
• Zhang, Qi
• Song, Qi
• Wang, Herui
• Cao, Xiaoyu
• Westlake, Timothy
• Yang, Kaiyong
• Rosenblum, Jared
• Yao, Yu
• Gilbert, Mark
• Zhuang, Zhengping

Titel

IMMU-38. TARGETING HYPOXIA DOWNSTREAM SIGNALING PROTEIN, CAIX FOR CAR-T CELL THERAPY AGAINST GLIOBLASTOMA (GBM)

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2018-11, Vol.20 (suppl_6), p.vi129-vi129

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2018

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Abstract BACKGROUND The need for novel therapies for GBM treatment is well established. While chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality, highly expressed unique cell surface antigens are essential. We postulated that tumor-specific surface antigens related to hypoxia signaling may have potential. Carbonic Anhydrase IX (CAIX) is active in settings of unbalanced pH driving proton transport to the extracellular medium in response to decreased oxygen tension. We provide evidence that CAIX is highly expressed in GBM and thus a potentially suitable target which we investigated using CAIX-specific CAR-T cells against GBM cells. METHODS Patient GBM tissues were evaluated for CAIX protein expression. Antitumor CAIX-specific CAR T cells were developed and tested against four GBM cell lines: U251, LN 229, T98G, and A172. Cytotoxicity of CAIX CAR-T cells was assessed using the levels of IFN-γ, TNF-α, and IL-2 released when co-cultured with tumor cells. Direct intra-tumor injection of CAR-T cells into intracranial GBM xenograft mouse model was used for in vivo testing. RESULTS We confirmed high expression of CAIX in of human GBM. The viral construct of CAIX-specific CAR-T cells generated was tested against GBM cell lines. In vitro, CAIX-specific CAR-T cells displayed enhanced GBM cells cytolysis and increased IFN-γ, TNF-α, and IL-2 production. The CAR-T cells showed a specific CAIX-dependent recognition of GBM cells. Direct intra-tumor injection of the CAR-T cells into an intracranial GBM xenograft mouse model efficiently suppressed the growth of GBM cells and significantly prolonged mouse survival. In approximately 20%, CAIX specific CAR-T cells completely eradicated GBM tumors. CONCLUSIONS The present study demonstrates the specificity of CAIX under hypoxic conditions in GBM. The results also show that CAIX represents a viable target for CAR-T cells and may be a promising strategy to treat GBM.