Department of Immunology, Health Faculty, Tehran University of Medical Sciences, Tehran, Iran.
School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
Stem Cell Rev Rep. 2019 Oct;15(5):619-636. doi: 10.1007/s12015-019-09901-7.
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.
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。
