Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all FDA-approved CAR-T cell therapies are autologous, and their widespread clinical application is limited by several challenges, such as complex individualized manufacturing, high costs, and the need for patient-specific selection. Allogeneic off-the-shelf CAR-engineered cell therapy offers promising potential due to its immediate availability, consistent quality, potency, and scalability in manufacturing. Nonetheless, significant challenges, including the risks of graft-versus-host disease (GvHD) and host cell-mediated allorejection, must be addressed. Strategies such as knocking out endogenous TCRs or using alternative therapeutic cells with low GvHD risk have shown promise in clinical trials aimed at reducing GvHD. However, mitigating allorejection remains critical for ensuring the long-term sustainability and efficacy of off-the-shelf cell products. In this review, we discuss the immunological basis of allorejection in CAR-engineered therapies and explore various strategies to overcome this challenge. We also highlight key insights from recent clinical trials, particularly related to the sustainability and immunogenicity of allogeneic CAR-engineered cell products, and address manufacturing considerations aimed at minimizing allorejection and optimizing the efficacy of this emerging therapeutic approach.

中文翻译：

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管理现成的 CAR 工程细胞疗法中的同种异体排斥反应。


嵌合抗原受体 （CAR） 工程 T （CAR-T） 细胞疗法彻底改变了各种疾病的治疗，包括癌症和自身免疫性疾病。然而，所有 FDA 批准的 CAR-T 细胞疗法都是自体的，其广泛的临床应用受到一些挑战的限制，例如复杂的个体化生产、高成本和需要根据患者进行选择。同种异体现成的 CAR 工程细胞疗法因其即时可用性、一致的质量、效力和制造可扩展性而具有广阔的潜力。尽管如此，必须解决重大挑战，包括移植物抗宿主病 （GvHD） 和宿主细胞介导的同种异体排斥的风险。敲除内源性 TCR 或使用低 GvHD 风险的替代治疗细胞等策略已在旨在降低 GvHD 的临床试验中显示出前景。然而，减轻同种异体排斥反应对于确保现成细胞产品的长期可持续性和有效性仍然至关重要。在这篇综述中，我们讨论了 CAR 工程疗法中同种异体排斥反应的免疫学基础，并探讨了克服这一挑战的各种策略。我们还强调了最近临床试验的关键见解，特别是与同种异体 CAR 工程细胞产品的可持续性和免疫原性相关的见解，并解决了旨在最大限度地减少同种异体排斥反应和优化这种新兴治疗方法疗效的生产注意事项。