Abstract：
Currently, CAR-T cell therapy relies on an individualized manufacturing process in which patient\'s own T cells are infused back into patients after being engineered and expanded ex vivo. Despite the astonishing outcomes of autologous CAR-T cell therapy, this approach is endowed with several limitations and drawbacks, such as high cost and time-consuming manufacturing process. Switching the armature of CAR-T cell therapy from autologous settings to allogeneic can overcome several bottlenecks of the current approach. Nevertheless, the use of allogeneic CAR-T cells is limited by the risk of life-threatening GvHD. Thus, in recent years, developing a method to move CAR-T cell therapy to allogeneic settings without the risk of GvHD has become a hot research topic in this field. Since the alloreactivity of αβ T-cell receptor (TCR) accounts for developing GvHD, several efforts have been made to disrupt endogenous TCR of allogeneic CAR-T cells using gene editing tools to prevent GvHD. Nonetheless, the off-target activity of gene editing tools and their associated genotoxicities, as well as the negative consequences of endogenous TCR disruption, are the main concerns of using this approach. As an alternative, CAR αβ-T cells can be replaced with other types of CAR-engineered cells that are capable of recognizing and killing malignant cells through CAR while avoiding the induction of GvHD. These alternatives include T cell subsets with restricted TCR repertoire (γδ-T, iNKT, virus-specific T, double negative T cells, and MAIT cells), killer cells (NK and CIK cells), non-lymphocytic cells (neutrophils and macrophages), stem/progenitor cells, and cell-free extracellular vesicles. In this review, we discuss how these alternatives can move CAR-based immunotherapy to allogeneic settings to overcome the bottlenecks of autologous manner without the risk of GvHD. We comprehensively discuss the pros and cons of these alternatives over the traditional CAR αβ-T cells in light of their preclinical studies and clinical trials.
摘要：
目前,CAR-T细胞疗法依赖于个性化的制造过程，在该过程中，患者自己的T细胞在经过体外工程化和扩增后被输注回患者体内。尽管自体CAR-T细胞疗法的结果令人惊讶，这种方法具有几个局限性和缺点，如高成本和耗时的制造过程。将CAR-T细胞疗法的骨架从自体设置切换到同种异体可以克服当前方法的几个瓶颈。然而，同种异体CAR-T细胞的使用受到危及生命的GvHD风险的限制.因此，近年来,开发一种将CAR-T细胞疗法转移到同种异体环境而没有GvHD风险的方法已成为该领域的研究热点。由于αβT细胞受体（TCR）的同种反应性导致了GvHD的发展，已经做出了一些努力,使用基因编辑工具来破坏同种异体CAR-T细胞的内源性TCR,以预防GvHD.尽管如此，基因编辑工具的脱靶活性及其相关的基因毒性，以及内源性TCR破坏的负面影响，是使用这种方法的主要关注点。作为替代,CARαβ-T细胞可以用能够通过CAR识别和杀死恶性细胞同时避免诱导GvHD的其他类型的CAR工程化细胞代替。这些替代方案包括具有限制性TCR库的T细胞亚群(γδ-T，iNKT,病毒特异性T，双阴性T细胞,和MAIT细胞)，杀伤细胞（NK和CIK细胞），非淋巴细胞（中性粒细胞和巨噬细胞），干细胞/祖细胞，和无细胞胞外囊泡。在这次审查中,我们讨论了这些替代方案如何将基于CAR的免疫疗法转移到同种异体环境中,以克服自体方式的瓶颈,而没有GvHD的风险.我们根据临床前研究和临床试验，全面讨论了这些替代品相对于传统CARαβ-T细胞的利弊。
