Department of Cellular Therapy, Department of Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
Methods Mol Biol. 2020;2115:407-417. doi: 10.1007/978-1-0716-0290-4_22.
Adoptive T cell therapy (ACT) using either chimeric antigen receptor (CAR)- or T cell receptor (TCR)-engineered lymphocytes has emerged as a promising strategy to treat cancer. However, this therapy is still facing enormous challenges such as poor quality of autologous T cells, T cell exhaustion, and the immune suppressive tumor microenvironments. Additionally, graft-versus-host disease is an issue that must be addressed to allow the use of allogeneic T cells. Strategies to overcome these therapeutic challenges using gene editing technology are now being developed. One strategy is to disrupt TCR and/or MHC expression in healthy donor T cells to generate T cells for universal use. Another strategy is to improve the quality of patient's T cells by eliminating either the expression of selected immune checkpoint receptors or negative regulators of TCR signaling and/or T-cell homeostasis. Here, we review the use of CRISPR-Cas9 platform in T cell engineering with a focus on the development of universal T cells and boosted autologous cells for next-generation ACT.
过继性 T 细胞疗法（ACT）采用嵌合抗原受体（CAR）或 T 细胞受体（TCR）工程化淋巴细胞，已成为治疗癌症的一种有前途的策略。然而，这种疗法仍面临着巨大的挑战，如自体 T 细胞质量差、T 细胞耗竭和免疫抑制性肿瘤微环境。此外，移植物抗宿主病是必须解决的问题，以允许使用同种异体 T 细胞。目前正在开发使用基因编辑技术克服这些治疗挑战的策略。一种策略是破坏健康供体 T 细胞中的 TCR 和/或 MHC 表达，以产生用于通用用途的 T 细胞。另一种策略是通过消除选定的免疫检查点受体或 TCR 信号和/或 T 细胞动态平衡的负调节剂的表达来提高患者 T 细胞的质量。在这里，我们综述了 CRISPR-Cas9 平台在 T 细胞工程中的应用，重点介绍了通用 T 细胞和增强的自体细胞在下一代 ACT 中的发展。
