Abbott Rebecca C, Verdon Daniel J, Gracey Fiona M, Hughes-Parry Hannah E, Iliopoulos Melinda, Watson Katherine A, Mulazzani Matthias, Luong Kylie, D'Arcy Colleen, Sullivan Lucy C, Kiefel Ben R, Cross Ryan S, Jenkins Misty R
Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.
The Department of Medical Biology The University of Melbourne Parkville VIC Australia.
Clin Transl Immunology. 2021 May 9;10(5):e1283. doi: 10.1002/cti2.1283. eCollection 2021.
The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade.
We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single-chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor-specific mutation found in glioblastoma. We use both functional assays and an orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells.
Our EGFRvIII-specific scFv was found to be of much higher affinity than reported comparators reverse-engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02-CAR T cells also mediate rapid and complete tumor elimination .
We present a novel EGFRvIII-specific CAR, with effective antitumor functions both in and in a xenograft model of human glioblastoma.
嵌合抗原受体（CAR）T细胞疗法在血液系统恶性肿瘤中的日益成功，正促使其在许多其他癌症类型中的应用重新焕发生机，并再次聚焦于其在实体瘤中的应用。我们展示了一种针对胶质母细胞瘤（一种侵袭性恶性胶质瘤，生存率极低且十多年来治疗方案一直未变）的新型CAR。
我们使用人类保留展示（ReD）抗体平台（Myrio Therapeutics）来鉴定一种新型单链可变片段（scFv），该片段可识别表皮生长因子受体突变体III型（EGFRvIII），这是在胶质母细胞瘤中发现的一种常见且肿瘤特异性的突变。我们使用功能测定和胶质母细胞瘤原位异种移植模型来检测我们名为GCT02的新型CAR的功能，该CAR由鼠源CAR T细胞靶向。
我们发现，我们的EGFRvIII特异性scFv的亲和力比从单克隆抗体反向工程得到的报道的对照物高得多。尽管亲和力更高，但GCT02 CAR T细胞的杀伤效果相当，但分泌的细胞因子量更低。此外，GCT02 - CAR T细胞还介导肿瘤的快速完全消除。
我们展示了一种新型的EGFRvIII特异性CAR，在人胶质母细胞瘤的原位和异种移植模型中均具有有效的抗肿瘤功能。
