Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells
Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells
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DOI：
10.1111/j.1365-2141.2005.05456.x
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发表时间：
2005-05-01
影响因子：
6.5
通讯作者：
Hawkins, RE
中科院分区：
文献类型：
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作者：
Cheadle, EJ;Gilham, DE;Hawkins, RE
肿瘤特异性T细胞过继免疫治疗是一项新兴技术，可能适用于广泛的癌症。然而，肿瘤可以通过多种机制避免T细胞介导的攻击，包括下调主要组织相容性复合体(MHC)。因此，设计T细胞直接靶向完整的蛋白抗原，从而绕过MHC呈递，可以促进T细胞靶向肿瘤细胞。对9例非霍奇金淋巴瘤(NHL)患者的外周血淋巴细胞进行基因修饰，成功地表达了CD19单链可变区(ScFv)与T细胞CD3Zeta信号分子融合的受体。这些T细胞对CD19(+)Raji Burkitt淋巴瘤细胞株具有功能活性。重要的是，来自9名NHL患者中7名的工程化T细胞有效地裂解了自体淋巴肿瘤活组织细胞。CD19在肿瘤上的表达水平与工程T细胞的有效杀伤作用之间存在明显的相关性。对于活检中CD19(+)细胞低或缺失的两名患者，没有观察到明显的杀伤作用。这些结果表明，在I期临床试验中，CD19(+)非霍奇金淋巴瘤患者将适合这种形式的治疗。
Adoptive immunotherapy with tumour-specific T cells is an emerging technology that may be applicable to a broad range of cancers. However, tumours can avoid T cell-mediated attack through multiple mechanisms including downregulation of major histocompatability complex ( MHC). Consequently, engineering T cells to target intact protein antigen directly, thus bypassing the need for MHC presentation, can facilitate T cell targeting of tumour cells. Peripheral blood lymphocytes from nine of nine patients with non-Hodgkin lymphoma (NHL) were successfully gene-modified to express a receptor consisting of a CD19 single chain variable fragment ( scFv) fused to the T cell CD3 zeta signalling molecule. These T cells were functionally active against the CD19(+) Raji Burkitt's lymphoma cell line. Importantly, engineered T cells from seven of nine NHL patients efficiently lysed autologous lymph node tumour biopsy cells. There was a clear correlation between levels of CD19 expression on the tumour and effective killing by the engineered T cells. For two patients with a low or absent CD19(+) cells within the biopsy, no significant killing was observed. These results demonstrate that patients with CD19(+) NHL would be suitable candidates for this form of therapy in the setting of a phase I clinical trial.