Selective Targeting of Glioblastoma with EGFRvIII/EGFR Bitargeted Chimeric Antigen Receptor T Cell
Selective Targeting of Glioblastoma with EGFRvIII/EGFR Bitargeted Chimeric Antigen Receptor T Cell
复制标题
使用 EGFRvIII/EGFR 双靶向嵌合抗原受体 T 细胞选择性靶向胶质母细胞瘤
DOI：
10.1158/2326-6066.cir-18-0044
复制
发表时间：
2018-11-01
影响因子：
10.1
通讯作者：
Li, Zonghai
中科院分区：
文献类型：
--
作者：
Jiang, Hua;Gao, Huiping;Li, Zonghai
胶质母细胞瘤中EGFRVIII [表皮生长因子受体（EGFR）的变体III突变体的异质表达对EGFRVIII特异性嵌合抗原受体受体启动T（Car T）细胞的临床反应具有重大影响。我们假设可以针对EGFRVIII和在肿瘤细胞上表达的EGFR的形式，而不是在正常细胞上表达的EGFR形式，而不会在不引起靶向型，非肿瘤的肿瘤毒性的情况下大大提高功效。因此，我们开发了一种人源化的单链抗体M27，具有单个特异性，该抗体与在野生型EGFR和EGFRVIII-ERDERCERDECH表达肿瘤细胞上的表位结合，但没有表达EGFR的正常细胞，包括原发性角化细胞，包括原发性角膜细胞，在上野生型EGFR的表达高度表达。 M27衍生的CAR T细胞有效地裂解了EGFR-VIII或EGFR过表达的肿瘤细胞，但对正常细胞没有明显的毒性。 M27-28BBZ汽车中的CD137（4-1BB）共刺激性细胞内结构域提供了与未包括时更高的肿瘤裂解活性（如M27-28Z汽车中）。 M27-28BBZ CAR T细胞也抑制了已建立的EGFR-OR或EGFRVIII-EGFRVIII-EVFRVIII-ENGRAMAMAMOMAMOMA异种移植物的生长。通过M27-28BBZ CAR T细胞有效抑制了通过混合EGFR和EGFR过表达的胶质母细胞瘤细胞产生的异质异种移植肿瘤的生长。 M27-28BBZ CAR T细胞输注后，小鼠在原位模型中的存活率显着延长。这些结果表明，肿瘤选择性的，性的抗EGFR/EGFRVIII CAR T细胞可能是治疗EGFR/EGFRVIII-ERDERCER表达胶质母细胞瘤患者的一种有希望的方式。 （c）2018 AACR。
CAR T cells targeting EGFR- and EGFRvIII-overexpressing tumor cells exhibit antitumor activity without toxicity toward normal EGFR-expressing cells in mouse glioblastoma models. This strategy may provide an avenue for future therapeutic development in EGFR- and EGFRvIII-overexpressing cancers. The heterogeneous expression of EGFRvIII [variant III mutant of epidermal growth factor receptor (EGFR)] in glioblastoma has significant impact on the clinical response to the treatment of EGFRvIII-specific chimeric antigen receptor–engineered T (CAR T) cells. We hypothesized that CAR T cells that could target both EGFRvIII and the form of EGFR expressed on tumor cells, but not EGFR on normal cells, would greatly improve efficacy without inducing on-target, off-tumor toxicity. Therefore, we developed a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed. M27-derived CAR T cells effectively lysed EGFRvIII- or EGFR-overexpressing tumor cells, but showed no observable toxicity on normal cells. Inclusion of the CD137 (4-1BB) costimulatory intracellular domain in the M27-28BBZ CAR provided CAR T cells with higher tumor lysis activity than when not included (as in the M27-28Z CAR). The growth of established EGFR- or EGFRvIII-overexpressing glioma xenografts was suppressed by M27-28BBZ CAR T cells as well. The growth of heterogeneic xenograft tumors, created by mixing EGFR- and EGFR-overexpressing glioblastoma cells, was also effectively inhibited by M27-28BBZ CAR T cells. The survival of mice in the orthotopic models was significantly prolonged after M27-28BBZ CAR T-cell infusion. These results suggested that tumor-selective, bitargeted anti-EGFR/EGFRvIII CAR T cells may be a promising modality for the treatment of patients with EGFR/EGFRvIII-overexpressing glioblastoma. Cancer Immunol Res; 6(11); 1314–26. ©2018 AACR.