Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor
Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor
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DOI：
10.1126/science.aav8692
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发表时间：
2019-07-12
期刊：
影响因子：
56.9
通讯作者：
Irvine, Darrell J.
中科院分区：
文献类型：
--
作者：
Ma, Leyuan;Dichwalkar, Tanmay;Irvine, Darrell J.
嵌合抗原受体-T细胞（CAR-T）疗法在血液恶性肿瘤的治疗中是有效的，但对实体瘤的疗效有限。在这里，我们展示了一种通过体内嵌合受体直接疫苗增强供体细胞来增强实体瘤中CAR-T功能的方法。我们设计了两亲性CAR-T配体（amph-配体），其在注射后被运输到淋巴结并装饰抗原呈递细胞的表面，从而在天然淋巴结微环境中引发CAR-T。Amph-配体加强引发了大规模CAR-T扩增，增加了供体细胞多功能性，并增强了多种免疫活性小鼠肿瘤模型中的抗肿瘤疗效。我们展示了两种将这种策略推广到任何嵌合抗原受体的方法，使这种简单的非人类白细胞抗原限制性方法能够增强CAR-T功能，并将其应用于现有的CAR-T设计。
Chimeric antigen receptor-Tcell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.