Marofi Faroogh, Motavalli Roza, Safonov Vladimir A, Thangavelu Lakshmi, Yumashev Alexei Valerievich, Alexander Markov, Shomali Navid, Chartrand Max Stanley, Pathak Yashwant, Jarahian Mostafa, Izadi Sepideh, Hassanzadeh Ali, Shirafkan Naghmeh, Tahmasebi Safa, Khiavi Farhad Motavalli
Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Stem Cell Res Ther. 2021 Jan 25;12(1):81. doi: 10.1186/s13287-020-02128-1.
CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal.
Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion.
Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.
嵌合抗原受体（CAR）是一种模拟受体，包含一个细胞外单链可变片段（scFv）、一个跨膜结构域，以及一个与共刺激信号相关的基于免疫受体酪氨酸的激活基序（ITAM）的细胞内区域。
嵌合抗原受体（CAR）T细胞是经过基因工程改造的T细胞，可表达一种受体，用于识别特定的表面标志物，这推动了血液疾病治疗的进展。CAR T细胞具有超生理特性，在T细胞表面表达后可作为“活药物”发挥即时和持续的作用。但是，它们在实体瘤治疗中的疗效尚未得到证实。实体瘤CAR T细胞治疗领域的关键挑战可概括为三个主要方面：在肿瘤中的识别、运输和存活。另一方面，免疫抑制性肿瘤微环境（TME）在分化和耗竭方面干扰T细胞活性，并且由于联合使用CAR和检查点阻断，以及抑制微环境中的其他抑制因子，在减少T细胞耗竭方面取得了非常有前景的结果。
如今，识别并克服与CAR T细胞功能障碍相关的机制对于建立能够严重增殖并裂解肿瘤细胞的CAR T细胞至关重要。在本综述中，我们讨论了实体瘤中CAR的信号传导和疗效，并评估了这一过程中最显著的障碍，并描述了旨在在非血液系统恶性肿瘤中获得有前景的治疗结果的最新治疗方法。
