Zeitschrift für Zellwissenschaft und Therapie
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Abstrakt

Adoptive Immunotherapy Against Malignant Glioma Using Survivin-specific CTLs Expanded by W6/32 Antibody-mediated Artificial Antigen-presenting Cells

Xiaoling Lu, Jiaqi Shi, Qin Yao, Jian He, Yuan Zhou, Hongbo Cai and Yongxiang Zhao

"Survivin is a bifunctional protein that acts as a suppressor of apoptosis and plays a central role in cell division. The protein is strongly expressed in the most common human neoplasms, has prognostic relevance for some of them and appears to be involved in tumor cell resistance to anticancer agents and ionizing radiation. Recently, survivin has been reported to be abundantly overexpressed in malignant glioma. The present study is a report of a novel approach of targeting malignant glioma with pSurvivin95-104-specific cytotoxic T-lymphocytes (CTLs). pSurvivin95-104-specific CTLs were induced from the peripheral blood lymphocytes (PBLs) of HLA-A2 positive healthy donors by multiple stimulations with W6/32 antibody-mediated artificial antigen-presenting cells (aAPCs) made by coating HLA-A2/pSurvivin95-104 tetramer mediated by W6/32 antibody, anti-CD28 antibody, 4-1BBL and CD83 molecules to cell-sized latex beads. After multiple stimulations and sorting, the expanded CTLs were analyzed for tetramer staining, IFN-γ production, CTL reactivity and adoptive immunotherapy experiments. Tetramer staining assay demonstrated the expanded CTLs specifically bound HLA-A2- pSurvivin95-104 tetramer. The CTLs specifically produced IFN-γ in response to W6/32 antibody-mediated aAPCs and exhibited specific lysis against T2 cells pulsed with the peptide and HLA-A2+ glioma cells expressing pSurvivin95-104, while HLA-A2- glioma cell lines that express survivin could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti-HLA class I monoclonal antibody. Intravenous injection of the expanded pSurvivin95-104-specific CTLs into nonobese diabetic– severe combined immunodeficiency (NOD/SCID) mice harboring glioma cells resulted in glioma cells elimination, whereas transfer of control T-cells was ineffective. These results show the expanded CTLs specific for pSurvivin95-104 peptide could be a potential target of specific immunotherapy for HLA-A2 patients with malignant glioma"