Siriraj Center for Regenerative Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Front Immunol. 2021 Sep 28;12:759558. doi: 10.3389/fimmu.2021.759558. eCollection 2021.
Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.
嵌合抗原受体 (CAR) T 细胞过继细胞疗法 (ACT) 在其他治疗方法难治的患者中具有令人印象深刻的临床疗效。然而，许多挑战阻碍了其临床应用。例如，接受化疗的患者由于淋巴细胞减少症，通常自体 T 细胞数量不足。长期扩增会导致 T 细胞耗竭，从而降低效应功能。在制造过程中也存在批次间差异，难以标准化和验证细胞产品。此外，该过程劳动强度大，成本高。生成通用现货 CAR T 细胞，提前准备并随时可用，可供任何患者广泛使用，这将是理想且更具成本效益的选择。人诱导多能干细胞 (iPSC) 提供了可再生的细胞来源，这些细胞可以经过基因工程改造，并分化为具有增强抗肿瘤细胞毒性的免疫细胞。这篇综述描述了 T 细胞生物学的基础知识、在 ACT 中的应用、iPSC 作为 T 细胞新来源的用途以及目前用于生成 T 细胞的分化策略，以及基因组工程在产生具有改善效应功能的下一代现货 T 细胞方面的最新进展。我们还讨论了该领域的挑战和未来展望，以期最终实现通用现货免疫治疗产品。
