Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.
Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.
复制标题
靶向EGFRVIII和IL-13Rα2的串联嵌合抗原受体（CAR）T细胞有效抗异质性胶质母细胞瘤。
DOI：
10.1093/noajnl/vdac185
复制
发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
嵌合抗原受体（CAR）T细胞在血液恶性肿瘤患者中取得了显着的反应;然而，这种治疗平台对胶质母细胞瘤（GBM）等实体瘤的潜力有限，这在很大程度上是由于在异质性疾病中靶向单一抗原。允许CAR T细胞同时接合多种抗原的策略可能会扩大治疗反应并减轻免疫逃逸的影响。在这里，我们开发了一种新型的双特异性串联CAR T（TanCART）细胞，能够同时靶向EGFRvIII和IL-13 R α2，这两种肿瘤抗原经常在GBM细胞表面发现，但在正常脑组织中完全不存在。我们采用了标准免疫学测定和多种原位临床前模型，包括患者来源的异种移植物，以证明这种方法对异质性肿瘤的疗效。串联CAR T细胞在体外对异质性GBM群体（包括患者来源的脑肿瘤培养物）显示出增强的细胞毒性（P <0.05）。与靶向单一抗原的CAR T细胞相比，通过串联构建体的双重抗原接合对于在异质性GBM的原位鼠模型（包括患者来源的异种移植物）中实现长期、完全和持久的应答是必要的（P < .05）。我们证明了TanCART对大脑中的异质性肿瘤是有效的。这些数据进一步证明了多特异性CAR T细胞在GBM和其他癌症治疗中的发展。
Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape. Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors. Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < .05). We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.
登录
查看更多内容
使用相同识别域的人类TCR和汽车介导的T细胞活性的比较。
DOI：
10.4049/jimmunol.1700236
发表时间：
2018-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Harris DT;Hager MV;Smith SN;Cai Q;Stone JD;Kruger P;Lever M;Dushek O;Schmitt TM;Greenberg PD;Kranz DM
通讯作者：
Kranz DM
第三代EGFRVIII特异性嵌合抗原受体的脑内递送有效地针对人神经胶质瘤。
影响因子：
2
作者：
Choi, Bryan D.;Suryadevara, Carter M.;Gedeon, Patrick C.;Herndon, James E., II;Sanchez-Perez, Luis;Bigner, Darell D.;Sampson, John H.
通讯作者：
Sampson, John H.
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
46.9
作者：
Choi, Bryan D.;Yu, Xiaoling;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
影响因子：
5.7
作者：
Debinski, W;Gibo, DM
通讯作者：
Gibo, DM