管理现成的嵌合抗原受体工程化细胞疗法中的同种异体排斥反应。
Managing allorejection in off-the-shelf CAR-engineered cell therapies.
作者信息
Li Yan-Ruide, Fang Ying, Niu Siyue, Chen Yuning, Lyu Zibai, Yang Lili
机构信息
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Mol Ther. 2024 Nov 26. doi: 10.1016/j.ymthe.2024.11.035.
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all US Food and Drug Administration (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 T cell receptors (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.
嵌合抗原受体（CAR）工程化T（CAR-T）细胞疗法彻底改变了包括癌症和自身免疫性疾病在内的多种疾病的治疗方式。然而，美国食品药品监督管理局（FDA）批准的所有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，如复杂的个体化制造、高成本以及对患者特异性选择的需求。异基因现成CAR工程化细胞疗法因其即时可用性、一致的质量、效力和制造的可扩展性而具有广阔的前景。尽管如此，必须解决包括移植物抗宿主病（GvHD）和宿主细胞介导的同种异体排斥反应风险在内的重大挑战。诸如敲除内源性T细胞受体（TCR）或使用具有低GvHD风险的替代治疗细胞等策略在旨在降低GvHD的临床试验中已显示出前景。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疗效仍然至关重要。在本综述中，我们讨论了CAR工程化疗法中同种异体排斥反应的免疫学基础，并探索了克服这一挑战的各种策略。我们还强调了近期临床试验的关键见解，特别是与异基因CAR工程化细胞产品的可持续性和免疫原性相关的见解，并讨论了旨在最小化同种异体排斥反应和优化这种新兴治疗方法疗效的制造考虑因素。
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