Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, United States; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Prog Mol Biol Transl Sci. 2019;164:293-327. doi: 10.1016/bs.pmbts.2019.07.004. Epub 2019 Jul 23.
CAR T cell therapy of cancers promises to revolutionize oncology by harnessing the powers of synthetic biology and immunotherapy in a single agent. CARs are synthetic receptors composed of an extracellular antigen binding domain and one or more intracellular signaling domains which act in concert to activate the T cell upon antigen recognition. CARs targeting B cell associated CD19 demonstrated robust in vivo cytolytic activity, expansion, and persistence upon antigen exposure paving the way for clinical application of this technology and ultimately FDA approval for pediatric and young adult acute lymphoblastic leukemia as well as patients with relapsed or refractory diffuse large B cell lymphoma. However, these successes have not yet been replicated in the arena of solid tumors. Unlike hematologic malignancies, solid tumors present numerous challenges in the form of an immunosuppressive tumor microenvironment. In this chapter, we will highlight clinical application of CAR T cells in solid tumors, discuss hurdles that have impeded CAR T cell function in these malignancies, and propose methods to overcome these limitations.
嵌合抗原受体 T 细胞疗法有望通过将合成生物学和免疫疗法的力量集中在一种药物中，从而彻底改变肿瘤学。CAR 是由细胞外抗原结合结构域和一个或多个细胞内信号转导结构域组成的合成受体，在抗原识别时协同作用激活 T 细胞。针对 B 细胞相关 CD19 的 CAR 在抗原暴露后表现出强大的体内细胞溶解活性、扩增和持久性，为该技术的临床应用铺平了道路，最终获得了 FDA 批准用于儿科和年轻成人急性淋巴细胞白血病以及复发性或难治性弥漫性大 B 细胞淋巴瘤患者。然而，这些成功尚未在实体肿瘤领域得到复制。与血液恶性肿瘤不同，实体肿瘤以免疫抑制性肿瘤微环境的形式带来了许多挑战。在本章中，我们将重点介绍 CAR T 细胞在实体肿瘤中的临床应用，讨论阻碍 CAR T 细胞在这些恶性肿瘤中发挥作用的障碍，并提出克服这些限制的方法。
