来那度胺通过增强免疫突触增强嵌合抗原受体修饰T细胞对抗表皮生长因子变异受体Ⅲ的...

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses


The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~ 50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3+ T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3+ T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

来那度胺通过增强免疫突触增强嵌合抗原受体修饰的T细胞对抗表皮生长因子变异受体Ⅲ的功能


表皮生长因子受体变异体III(EGFRvIII)只专门在50%的多形性胶质母细胞瘤表面表达。这种
变异体能够以配体依赖的形式强烈而持久的激活PI3K-AKT信号途径，增强致瘤性、细胞活
性和抗放化疗的能力。我们的小组制备了一个特异性靶向EGFRvIII的重组单链可变区域
（scFv）抗体，简称3C10-scFv。在目前的研究中，我们构建了一个慢病毒载体转导的嵌合
抗原受体（CAR），包括3C10单链抗体，CD3ζ，CD28和4-1BB（3c10-car）。3C10-CAR
转导到外周血单个核细胞（PBMCs）和特异性溶解表达EGFRvIII的CD3+T细胞。此外，我
们发现CAR CD3+T细胞在用3C10-CAR PBMCs 处理的小鼠体内向多形性胶质母细胞瘤颅
内移植瘤迁移。一个重要的新的发现是，沙利度胺的衍生物来那度胺能够诱导3C10-CAR
PBMC增殖，并能增强细胞体内抗肿瘤的持续性。来那度胺也展示了能够增强由CD11a和纤
维蛋白聚合决定的效应细胞和靶细胞之间的免疫突触。总的来说，慢病毒转导的靶向
EGFRvIII的嵌合抗原受体效应体显示了明确的效果，来那度胺甚至通过增强免疫突触形成
来增强CAR-T细胞疗法。