肿瘤细胞治疗研究
英文原题：Potential alternatives to αβ-T cells to prevent graft-versus-host disease (GvHD) in allogeneic chimeric antigen receptor (CAR)-based cancer immunotherapy: A comprehensive review.
目前，CAR-T细胞疗法依赖于个体化制造过程，即患者自身的T细胞在体外经过工程改造和扩增后，再回输给患者。
目前，CAR-T细胞疗法依赖于个体化制造流程，即患者自身的T细胞经过体外工程化改造和扩增后回输给患者。尽管自体CAR-T细胞疗法取得了令人瞩目的疗效，但该方法仍存在若干局限性和缺点，例如成本高昂和制造过程耗时。将CAR-T细胞疗法的核心从自体模式转变为异体模式，可以克服当前方法的若干瓶颈。然而，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，开发一种能够在无GvHD风险的情况下将CAR-T细胞疗法推向异体模式的方法，已成为该领域的研究热点。由于T细胞受体（TCR）的同种异体反应性是导致GvHD的原因，研究者已做出多项努力，利用基因编辑工具破坏异体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破坏带来的负面后果，是使用该方法的主要顾虑。作为替代方案，CAR-T细胞可被其他类型的CAR工程化细胞所取代，这些细胞能够通过CAR识别并杀伤恶性细胞，同时避免诱导GvHD。这些替代方案包括TCR库受限的T细胞亚群（γδ-T、iNKT、病毒特异性T、双阴性T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，以及无细胞胞外囊泡。在这篇综述中，我们讨论了这些替代方案如何将基于CAR的免疫治疗推向异体环境，以克服自体方式的瓶颈，同时避免GvHD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较于传统CAR-T细胞的优缺点。
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 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 -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 ( -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 -T cells in light of their preclinical studies and clinical trials.
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