用于靶向Fn14阳性胶质母细胞瘤的表达RevCAR的免疫效应细胞。

RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma.

作者信息

Saleh Haidy A, Mitwasi Nicola, R Loureiro Liliana, Kegler Alexandra, Soto Karla Elizabeth González, Hoffmann Lydia, Crespo Eugenia, Arndt Claudia, Bergmann Ralf, Bachmann Michael, Feldmann Anja

机构信息

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany.

Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, D-01307, Dresden, Germany.

出版信息

Cancer Gene Ther. 2024 Sep;31(9):1323-1334. doi: 10.1038/s41417-024-00766-8. Epub 2024 Apr 6.

Abstract

In recent studies, we have established the unique adapter chimeric antigen receptor (CAR) platform RevCAR which uses, as an extracellular CAR domain, a peptide epitope instead of an antibody domain. RevCAR adapters (termed RevCAR target modules, RevTMs) are bispecific antibodies that enable the reversible ON/OFF switch of the RevCAR system, improving the safety compared to conventional CARs. Here, we describe for the first time its use for retargeting of both T and NK-92 cells. In addition, we describe the development and preclinical validation of a novel RevTM for targeting of the fibroblast growth factor-inducible 14 (Fn14) surface receptor which is overexpressed on Glioblastoma (GBM) cells, and therefore serves as a promising target for the treatment of GBM. The novel RevTM efficiently redirects RevCAR modified T and NK-92 cells and leads to the killing of GBM cells both in vitro and in vivo. Tumor cell killing is associated with increased IL-2, TNF-α and/or IFN-γ secretion. Hence, these findings give an insight into the complementary potential of both RevCAR T and NK-92 systems as a safe and specific immunotherapeutic approach against GBM.

摘要

在最近的研究中,我们建立了独特的衔接子嵌合抗原受体(CAR)平台RevCAR,该平台使用肽表位而非抗体结构域作为细胞外CAR结构域。RevCAR衔接子(称为RevCAR靶标模块,RevTMs)是双特异性抗体,可实现RevCAR系统的可逆开/关切换,与传统CAR相比提高了安全性。在此,我们首次描述了其用于重定向T细胞和NK-92细胞的情况。此外,我们描述了一种新型RevTM的开发和临床前验证,该RevTM用于靶向在胶质母细胞瘤(GBM)细胞上过度表达的成纤维细胞生长因子诱导14(Fn14)表面受体,因此是治疗GBM的一个有前景的靶点。新型RevTM有效地重定向RevCAR修饰的T细胞和NK-92细胞,并导致GBM细胞在体外和体内被杀伤。肿瘤细胞杀伤与IL-2、TNF-α和/或IFN-γ分泌增加有关。因此,这些发现深入了解了RevCAR T细胞和NK-92系统作为针对GBM的安全且特异性免疫治疗方法的互补潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a69c/11405279/48b30116cd1a/41417_2024_766_Fig1_HTML.jpg

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