德国BioNTech公司U. Sahin团队发现,一种RNA疫苗能够促进claudin-CAR-T细胞扩增并对抗实体瘤。相关论文2020年1月2日在线发表在《科学》上。
研究人员发现,CLDN6蛋白(developmentally regulated tight junction protein claudin 6)可作为实体瘤中的CAR靶标,以及克服体内无效的CAR-T细胞刺激的策略。研究人员证明了一种纳米颗粒RNA疫苗(旨在将CAR抗原在全身范围内传递到淋巴区室)能够刺激过继转移的CAR-T细胞。天然折叠靶标在驻留树突状细胞上的存在促进了CAR-T细胞的同源和选择性扩增。在亚治疗性CAR-T细胞剂量下,可改善CAR-T细胞的植入率,并在难以治疗的小鼠模型中使大型肿瘤消退。
据悉,嵌合抗原受体(CAR)-T细胞已在B细胞恶性肿瘤患者中显示出功效。然而,它们在实体瘤中的应用面临挑战,包括有限的癌症特异性靶标和过继转移CAR-T细胞的非持久性。
附:英文原文
Title: An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
Author: K. Reinhard, B. Rengstl, P. Oehm, K. Michel, A. Billmeier, N. Hayduk, O. Klein, K. Kuna, Y. Ouchan, S. Wll, E. Christ, D. Weber, M. Suchan, T. Bukur, M. Birtel, V. Jahndel, K. Mroz, K. Hobohm, L. Kranz, M. Diken, K. Kühlcke, . Türeci, U. Sahin
Issue&Volume: 2020/01/02
Abstract: Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet their application for solid tumors has challenges that include limited cancer-specific targets and non-persistence of adoptively transferred CAR-T cells. Here we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors, and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident dendritic cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at sub-therapeutic CAR-T cell doses.
DOI: 10.1126/science.aay5967
Source: https://science.sciencemag.org/content/early/2019/12/30/science.aay5967