目前，CAR-T细胞疗法依赖于个体化的制造过程，在该过程中，患者自身的T细胞在离体工程和扩增后被输回患者体内。尽管自体 CAR-T 细胞疗法取得了惊人的效果，但这种方法存在一些局限性和缺点，例如成本高且制造过程耗时。将 CAR-T 细胞疗法的核心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且无GvHD风险的方法已成为该领域的热门研究课题。由于 αβ T 细胞受体 (TCR) 的同种异体反应性是 GvHD 发生的原因，因此人们已经做出了一些努力，利用基因编辑工具破坏同种异体 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动及其相关的基因毒性，以及内源性 TCR 破坏的负面后果，是使用这种方法的主要问题。作为替代方案，CAR αβ-T 细胞可以替换为其他类型的 CAR 工程细胞，这些细胞能够通过 CAR 识别和杀死恶性细胞，同时避免诱导 GvHD。这些替代方案包括具有受限 TCR 功能的 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/祖细胞和无细胞细胞外囊泡。在这篇综述中，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，而不存在 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方案相对于传统 CAR αβ-T 细胞的优缺点。版权所有 © 2024 Elsevier GmbH。版权所有。

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.Copyright © 2024 Elsevier GmbH. All rights reserved.