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一种完全人源化的CD3 ζ链信号受体,可引导外周血T细胞对癌胚抗原阳性肿瘤细胞进行特异性裂解。

An entirely humanized CD3 zeta-chain signaling receptor that directs peripheral blood t cells to specific lysis of carcinoembryonic antigen-positive tumor cells.

作者信息

Hombach A, Schneider C, Sent D, Koch D, Willemsen R A, Diehl V, Kruis W, Bolhuis R L, Pohl C, Abken H

机构信息

Klinik I für Innere Medizin, Labor Tumorgenetik, Universität zu Köln, Köln, Germany.

出版信息

Int J Cancer. 2000 Oct 1;88(1):115-20.

Abstract

Recombinant T-cell receptors with antibody-like specificity for tumor-associated antigens are successfully used to direct the cytolytic activity of T cells toward tumor cells. Clinical application, however, needs to comply with the low immunogenicity of the recombinant receptor, efficient gene transfer into peripheral blood T cells, and enrichment of receptor-grafted cells. Here, we address these issues and describe an entirely humanized immune receptor for use in adoptive immunotherapy of colorectal carcinoma. The receptor consists of a single-chain antibody (scFv) binding domain specific for carcinoembryonic antigen (CEA), the IgG hinge and CH2/CH3 (Fc) joining region, and the transmembrane and intracellular CD3 zeta signaling chain. To express the receptor in peripheral blood T cells, both GALV envelope and MuLV 4070A pseudotyped retrovirus turned out to be equally efficient, with transduction efficiencies of about 5% to 40%, depending on the lymphocyte donor. Furthermore, receptor-grafted T cells could be 2- to 6-fold enriched by magnetic activated cell sorting, utilizing an antibody directed to the extracellular IgG domain of the receptor. Upon co-culture with CEA(+) tumor cells, receptor-grafted T cells are specifically and efficiently activated to cytolysis and IFN-gamma secretion, demonstrating their feasibility for the adoptive immunotherapy of CEA(+) carcinomas.

摘要

对肿瘤相关抗原有抗体样特异性的重组T细胞受体已成功用于引导T细胞对肿瘤细胞的细胞溶解活性。然而,临床应用需要符合重组受体的低免疫原性、将基因有效转移到外周血T细胞以及富集受体移植细胞。在此,我们解决这些问题并描述一种完全人源化的免疫受体,用于结直肠癌的过继性免疫治疗。该受体由对癌胚抗原(CEA)具有特异性的单链抗体(scFv)结合结构域、IgG铰链区和CH2/CH3(Fc)连接区以及跨膜和细胞内CD3ζ信号链组成。为了在外周血T细胞中表达该受体,GALV包膜和MuLV 4070A假型逆转录病毒均显示出相同的效率,转导效率约为5%至40%,具体取决于淋巴细胞供体。此外,利用针对受体细胞外IgG结构域的抗体,通过磁激活细胞分选可将受体移植的T细胞富集2至6倍。与CEA(+)肿瘤细胞共培养时,受体移植的T细胞被特异性且有效地激活以进行细胞溶解和分泌IFN-γ,证明了它们用于CEA(+)癌过继性免疫治疗的可行性。

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