「抗癌管家」全球肿瘤免疫治疗信息精选【第一期】—抗癌管家( 八 )

摘要：RNA疫苗(CARVac)在临床前阶段实现改善CAR-T细胞的抗肿瘤作用，人体试验有待开展验证。
关键字：RNA疫苗、CAR-T、实体瘤
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原文：
CAR-T细胞已在B细胞恶性肿瘤患者中显示出疗效。然而，它们在治疗实体瘤中还面临着不少挑战，包括癌症特异性实体肿瘤靶标很少、CAR-T细胞向实体瘤中的浸润效率低以及CAR -T细胞的持久性不足。抗癌管家，我们一起抗癌，治愈癌症不是梦。此研究应用了CLDN6作为实体瘤的CAR靶向以刺激体内CAR-T细胞的生长。科学家们也发现一种RNA疫苗，可以将CAR抗原传递到淋巴，增加CAR-T细胞的生长、扩张和浸润性。即使是在亚治疗性CAR-T细胞剂量下，也可使肿瘤在难治性小鼠体内消退。
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.
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来源：《Science》
发生区域：美国
发布时间：2020.2.5
摘要：CRISPR（编辑DNA）和T细胞疗法结合为癌症免疫疗法领域开创了新篇章。虽预后效果不好，但表明了此疗法的安全性。
关键字：CRISPR、T细胞、联合疗法
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原文:
CRISPR-Cas9基因编辑为增强人类T细胞抵抗癌症赋予了强大的助力。这项新的研究是一项人类首次的I期临床试验，包括3名难治性癌症患者，以测试改造T细胞的CRISPR-Cas9基因的安全性和可行性。结果虽然是有限的，因为3位病人的病情都已进展，但是癌症学家Carl June补充道：虽然这项研究并没有完全治愈病人，但是起码证明了它的整个试验过程是安全以及可行的，对未来癌症研究也是重要的一个转折。
CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase I clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene-editing for cancer immunotherapy.