预防同种异体嵌合抗原受体 (CAR) 为基础的癌症免疫疗法中移植物抗宿主病 (GvHD) 的 αβ-T 细胞潜在替代物:全面综述。

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.

机构信息

College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China; Department of Neurology, Xinxiang First Peoples Hospital, Xinxiang 453100, China.

College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China.

出版信息

Pathol Res Pract. 2024 Oct;262:155518. doi: 10.1016/j.prp.2024.155518. Epub 2024 Aug 10.

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 细胞疗法依赖于个体化的制造过程,其中患者自身的 T 细胞在经过工程化和体外扩增后再回输给患者。尽管自体 CAR-T 细胞疗法的结果令人惊讶,但这种方法存在几个限制和缺点,例如成本高和制造过程耗时。将 CAR-T 细胞疗法的基础从自体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移植物抗宿主病 (GvHD) 风险的限制。因此,近年来,开发一种方法将 CAR-T 细胞疗法转移到同种异体环境而不产生 GvHD 风险已成为该领域的热门研究课题。由于 αβ T 细胞受体 (TCR) 的同种异体反应性导致 GvHD 的发生,因此已经做出了一些努力,使用基因编辑工具破坏同种异体 CAR-T 细胞的内源性 TCR,以防止 GvHD。尽管如此,基因编辑工具的脱靶活性及其相关的遗传毒性,以及内源性 TCR 破坏的负面后果,是使用这种方法的主要关注点。作为替代方案,CAR αβ-T 细胞可以被其他类型的 CAR 工程细胞取代,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 TCR repertoire 受限的 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/祖细胞和细胞外囊泡。在这篇综述中,我们讨论了如何通过这些替代方案将基于 CAR 的免疫疗法转移到同种异体环境中,从而克服自体方式的瓶颈,同时避免 GvHD 的风险。我们根据这些替代方案的临床前研究和临床试验,全面讨论了它们相对于传统 CAR αβ-T 细胞的优缺点。

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