Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Japan.
Blood. 2012 Jan 12;119(2):368-76. doi: 10.1182/blood-2011-06-360354. Epub 2011 Oct 24.
Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia.
极光激酶 A（AURKA）在白血病中过表达。此前，我们证明了 AURKA 特异性 CD8(+) T 细胞能够特异性和选择性地杀伤白血病细胞，这表明 AURKA 是免疫治疗的一个极好靶点。在这项研究中，我们研究了使用表达 HLA-A0201 限制性 AURKA(207-215)-特异性 T 细胞受体（TCR）的重定向 T 细胞进行过继治疗的可行性。逆转录病毒转导的 T 细胞识别相关肽脉冲但不识别对照靶细胞。此外，TCR 重定向的 CD8(+) T 细胞以 HLA-A0201 限制性方式杀伤 AURKA 过表达的人白血病细胞，但不杀伤 HLA-A*0201(+)正常细胞，包括造血祖细胞。此外，AURKA(207-215)-特异性 TCR 转导的 CD4(+) T 细胞表现出靶标反应性 Th1 细胞因子产生。最后，AURKA(207-215)-特异性 TCR 转导的 CD8(+) T 细胞在异种移植小鼠模型中显示出抗白血病疗效。总之，这些数据表明基于重定向 T 细胞的 AURKA 特异性免疫疗法治疗人类白血病的可行性。
