Engineering NK Cells Modified With an EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1α-secreting Glioblastoma.
Engineering NK Cells Modified With an EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1α-secreting Glioblastoma.
复制标题
用EGFRVIII特异性嵌合抗原受体改装以过表达CXCR4的工程NK细胞可改善CXCL12/SDF-1α分泌胶质母细胞瘤的免疫疗法。
DOI：
10.1097/cji.0000000000000082
复制
发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Temme A
中科院分区：
文献类型：
--
作者：
Müller N;Michen S;Tietze S;Töpfer K;Schulte A;Lamszus K;Schmitz M;Schackert G;Pastan I;Temme A
NK细胞是一种很有前途的肿瘤辅助免疫治疗效应细胞。到目前为止，一些临床前研究已经证明了基因工程NK细胞的可行性，这些细胞在嵌合抗原受体（CARs）的表达后被重定向到NK细胞耐药的肿瘤中。然而，我们推断，使用car修饰NK细胞的免疫治疗的效率严重依赖于向肿瘤部位的有效迁移，并且可能通过植入肿瘤释放的趋化因子特异性受体来提高。基于dnax活化蛋白12 (DAP12)，一种参与激活NK细胞受体信号转导的信号适配器分子，我们构建了EGFRvIII- car，命名为MR1.1-DAP12，它在体外赋予NK细胞对EGFRvIII+胶质母细胞瘤细胞的特异性细胞毒性，并建立了皮下U87-MGEGFRvIII肿瘤异种移植物。到目前为止，与使用itam缺陷CAR转导的NK细胞相比，输注表达MR1.1-DAP12的NK细胞导致肿瘤生长中度但显著延迟，中位生存时间增加。值得注意的是，这些egfrviii特异性NK细胞与趋化因子受体CXCR4的进一步基因工程赋予了CXCL12/SDF-1α分泌U87-MG胶质母细胞瘤细胞的特异性趋化性。此外，与仅表达egfrviii特异性CAR或模拟对照的NK细胞治疗异种移植物相比，这种NK细胞的管理导致许多小鼠的肿瘤完全缓解，生存率显著提高。我们得出结论，趋化因子受体工程NK细胞与肿瘤特异性CAR的同时表达是一个有希望的工具，以改善过继性肿瘤免疫治疗。
NK cells are promising effector cells for adjuvant immunotherapy of cancer. So far, several preclinical studies have shown the feasibility of gene-engineered NK cells, which upon expression of chimeric antigen receptors (CARs) are redirected to otherwise NK-cell resistant tumors. Yet, we reasoned that the efficiency of an immunotherapy using CAR-modified NK cells critically relies on efficient migration to the tumor site and might be improved by the engraftment of a receptor specific for a chemokine released by the tumor. Based on the DNAX-activation protein 12 (DAP12), a signaling adapter molecule involved in signal transduction of activating NK cell receptors, we constructed an EGFRvIII-CAR, designated MR1.1-DAP12 which confers specific cytotoxicity of NK cell towards EGFRvIII+ glioblastoma cells in vitro and to established subcutaneous U87-MGEGFRvIII tumor xenografts. So far, infusion of NK cells with expression of MR1.1-DAP12 caused a moderate but significantly delayed tumor growth and increased median survival time when compared to NK cells transduced with an ITAM-defective CAR. Notably, the further genetic engineering of these EGFRvIII-specific NK cells with the chemokine receptor CXCR4 conferred a specific chemotaxis to CXCL12/SDF-1α secreting U87-MG glioblastoma cells. Moreover, the administration of such NK cells resulted in complete tumor remission in a number of mice and a significantly increased survival when compared to the treatment of xenografts with NK cells expressing only the EGFRvIII-specific CAR or mock control. We conclude that chemokine receptor engineered NK cells with concomitant expression of a tumor-specific CAR are a promising tool to improve adoptive tumor immunotherapy.