肿瘤细胞治疗研究
英文原题：In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.
使用嵌合抗原受体（CAR）的 CAR T 细胞疗法为多种血液系统恶性肿瘤的治疗带来了根本性转变，产生了高缓解率和持久缓解。
使用嵌合抗原受体（CAR）的CAR-T细胞疗法彻底改变了多种血液系统恶性肿瘤的治疗格局，产生了高缓解率和持久缓解。然而，传统的体外制造受限于复杂的处理步骤、高成本、产品质量的差异性以及限制患者入选资格的临床相关延迟。体内制造作为一种下一代方法已经出现，该方法在患者体内直接对免疫细胞进行重编程，无需外源性处理和培养。该策略使用病毒性和非病毒性递送平台，包括慢病毒载体、腺相关病毒、脂质纳米颗粒和靶向聚合物系统，并结合DNA、mRNA以及诸如基于CRISPR的技术等基因组编辑工具。早期可行性数据主要由临床前模型和转化研究支持，而由于潜在的免疫毒性、脱靶转导和监管挑战，安全性仍然是核心关切。本综述重点介绍能够实现体内CAR-T细胞生成的关键工程策略，总结新兴的临床研究与发展，并讨论将体内CAR-T细胞疗法扩展为可规模化免疫治疗平台的未来机遇。
CAR T-cell therapy using chimeric antigen receptors (CARs) has provided a radical shift in the treatment of several hematological malignancies, producing high response rates and durable remissions. However, conventional ex vivo manufacturing is limited by complex processing steps, high costs, variability in product quality, and clinically relevant delays that restrict patient eligibility. In vivo manufacturing has emerged as a next-generation approach in which immune cells are reprogrammed directly within the patient, eliminating the need for exogenous handling and culture. This strategy uses viral and non-viral delivery platforms, including lentiviral vectors, adeno-associated viruses, lipid nanoparticles, and targeted polymer systems, together with DNA, mRNA, and genome editing tools such as CRISPR-based technologies. Early feasibility data are supported mainly by preclinical models and translational studies, while safety remains a central concern due to potential immunotoxicity, off-target transduction, and regulatory challenges. This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.
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