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An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
Science ( IF 56.9 ) Pub Date : 2020-01-02 , DOI: 10.1126/science.aay5967
Katharina Reinhard 1 , Benjamin Rengstl 1 , Petra Oehm 1 , Kristina Michel 1 , Arne Billmeier 1 , Nina Hayduk 1 , Oliver Klein 1 , Kathrin Kuna 1 , Yasmina Ouchan 1 , Stefan Wöll 1 , Elmar Christ 1 , David Weber 2 , Martin Suchan 2 , Thomas Bukur 2 , Matthias Birtel 1 , Veronika Jahndel 1 , Karolina Mroz 1 , Kathleen Hobohm 1 , Lena Kranz 1 , Mustafa Diken 2 , Klaus Kühlcke 1 , Özlem Türeci 1 , Ugur Sahin 1, 2, 3
Affiliation  

A one-two, CAR-T cell punch Chimeric antigen receptor (CAR)–T cells have been clinically effective in killing certain hematological malignancies, but achieving long-term patient responses for solid tumors remains a challenge. Reinhard et al. describe a two-part “CARVac” strategy to overcome poor CAR-T cell stimulation and responses in vivo. They introduce the tight junction protein claudin 6 (CLDN6) as a new CAR-T cell target and designed a nanoparticulate RNA vaccine encoding a chimeric receptor directed toward CLDN6. This lipoplex RNA vaccine promotes CLDN6 expression on the surface of dendritic cells, which in turn stimulates and enhances the efficacy of CLDN6-CAR-T cells for improved tumor therapy. Science, this issue p. 446 A nanoparticle RNA vaccine strategy targets chimeric antigen receptor (CAR)–T cells to solid tumors in difficult-to-treat mouse models. 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 nonpersistence 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 antigen-presenting 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 subtherapeutic CAR-T cell doses.

中文翻译:

RNA疫苗驱动claudin-CAR-T细胞对实体瘤的扩增和功效

一对二的 CAR-T 细胞打孔嵌合抗原受体 (CAR)-T 细胞在临床上可有效杀死某些血液系统恶性肿瘤,但实现患者对实体瘤的长期反应仍然是一个挑战。莱因哈德等人。描述了一种由两部分组成的“CARVac”策略,以克服体内较差的 CAR-T 细胞刺激和反应。他们将紧密连接蛋白密蛋白 6 (CLDN6) 作为新的 CAR-T 细胞靶标引入,并设计了一种纳米颗粒 RNA 疫苗,其编码针对 CLDN6 的嵌合受体。这种脂质复合物 RNA 疫苗可促进树突细胞表面的 CLDN6 表达,进而刺激和增强 CLDN6-CAR-T 细胞改善肿瘤治疗的功效。科学,这个问题 p。446 纳米颗粒 RNA 疫苗策略将嵌合抗原受体 (CAR)-T 细胞靶向难以治疗的小鼠模型中的实体瘤。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疗效。然而,它们在实体瘤中的应用面临挑战,包括癌症特异性靶点有限和过继转移的 CAR-T 细胞不存在。在这里,我们介绍了发育调控的紧密连接蛋白密蛋白 6(CLDN6)作为实体瘤中的 CAR 靶点,以及一种克服体内 CAR-T 细胞刺激效率低下的策略。我们证明了一种纳米颗粒 RNA 疫苗,设计用于将 CAR 抗原全身递送到淋巴区室,刺激过继转移的 CAR-T 细胞。在常驻抗原呈递细胞上呈递天然折叠的靶标促进了 CAR-T 细胞的同源和选择性扩增。在亚治疗剂量的 CAR-T 细胞剂量下,改善了 CAR-T 细胞的植入和难以治疗的小鼠模型中大肿瘤的消退。
更新日期:2020-01-02
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