研究發(fā)現(xiàn)：RNA疫苗可增加CAR-T細(xì)胞對(duì)實(shí)體瘤療效
德國(guó)BioNTech公司U. Sahin團(tuán)隊(duì)發(fā)現(xiàn)，一種RNA疫苗能夠促進(jìn)claudin-CAR-T細(xì)胞擴(kuò)增并對(duì)抗實(shí)體瘤。相關(guān)論文2020年1月2日在線發(fā)表在《科學(xué)》上。
研究人員發(fā)現(xiàn)，CLDN6蛋白（developmentally regulated tight junction protein claudin 6）可作為實(shí)體瘤中的CAR靶標(biāo)，以及克服體內(nèi)無效的CAR-T細(xì)胞刺激的策略。研究人員證明了一種納米顆粒RNA疫苗（旨在將CAR抗原在全身范圍內(nèi)傳遞到淋巴區(qū)室）能夠刺激過繼轉(zhuǎn)移的CAR-T細(xì)胞。天然折疊靶標(biāo)在駐留樹突狀細(xì)胞上的存在促進(jìn)了CAR-T細(xì)胞的同源和選擇性擴(kuò)增。在亞治療性CAR-T細(xì)胞劑量下，可改善CAR-T細(xì)胞的植入率，并在難以治療的小鼠模型中使大型腫瘤消退。
據(jù)悉，嵌合抗原受體（CAR）-T細(xì)胞已在B細(xì)胞惡性腫瘤患者中顯示出功效。然而，它們?cè)趯?shí)體瘤中的應(yīng)用面臨挑戰(zhàn)，包括有限的癌癥特異性靶標(biāo)和過繼轉(zhuǎn)移CAR-T細(xì)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
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