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实体瘤挑战与 CAR T 细胞工程新视角。

Solid Tumors Challenges and New Insights of CAR T Cell Engineering.

机构信息

Department of Immunology, Health Faculty, Tehran University of Medical Sciences, Tehran, Iran.

School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.

出版信息

Stem Cell Rev Rep. 2019 Oct;15(5):619-636. doi: 10.1007/s12015-019-09901-7.

Abstract

Adoptive cell therapy using CAR T cells has emerged as a novel treatment strategy with promising results against B cell malignancies; however, CAR T cells have not shown much success against solid malignancies. There are several obstacles which diminish the efficacy of CAR T cells, but the immunosuppressive tumor microenvironment (TME) of the tumor stands out as the most important factor. TME includes Tumor-Associated Stroma, Immunosuppressive cells and cytokines, tumor hypoxia and metabolism, and Immune Inhibitory Checkpoints which affect the CAR T cell efficacy and activity in solid tumors. A precise understanding of the TME could pave the way to engineer novel modifications of CAR T cells which can overcome the immunosuppressive TME. In this review, we will describe different sections of the TME and introduce novel approaches to improve the CAR T cells potential against solid tumors based on recent clinical and preclinical data. Also, we will provide new suggestions on how to modify CARs to augment of CAR T cells efficacy. Since there are also some challenges beyond the TME that are important for CAR function, we will also discuss and provide data about the improvement of CAR T cells trafficking and delivery to the tumor site and how to solve the problem of tumor antigen heterogeneity.

摘要

嵌合抗原受体 T 细胞(CAR T 细胞)过继细胞疗法已成为一种新的治疗策略,在对抗 B 细胞恶性肿瘤方面显示出了很好的效果;然而,CAR T 细胞在对抗实体恶性肿瘤方面并没有取得太大的成功。有几个障碍降低了 CAR T 细胞的疗效,但肿瘤的免疫抑制肿瘤微环境(TME)是最重要的因素。TME 包括肿瘤相关基质、免疫抑制细胞和细胞因子、肿瘤缺氧和代谢以及免疫抑制检查点,这些因素都会影响 CAR T 细胞在实体肿瘤中的疗效和活性。对 TME 的精确理解可能为设计新型的 CAR T 细胞修饰方法铺平道路,以克服免疫抑制的 TME。在这篇综述中,我们将描述 TME 的不同部分,并根据最近的临床前和临床数据,介绍改善 CAR T 细胞对实体肿瘤潜力的新方法。此外,我们还将就如何修饰 CAR 以增强 CAR T 细胞的疗效提供新的建议。由于 TME 之外还有一些对 CAR 功能很重要的挑战,我们也将讨论并提供关于改善 CAR T 细胞向肿瘤部位的迁移和递送的相关数据,以及如何解决肿瘤抗原异质性的问题。

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