Abken Hinrich
Leibniz Institute for Immunotherapy, Genetic Immunotherapy Division, Regensburg, Germany.
Genetic Immunotherapy, University of Regensburg, Regensburg, Germany.
Nat Rev Gastroenterol Hepatol. 2025 Apr 14. doi: 10.1038/s41575-025-01062-y.
Despite multimodal treatment options, most gastrointestinal cancers are still associated with high mortality rates and poor responsiveness to immunotherapy. The unprecedented efficacy of chimeric antigen receptor (CAR)-engineered T cells in the treatment of haematological malignancies raised interest in translating CAR T cell therapies to the treatment of gastrointestinal cancers. Treatment of solid cancers with canonical CAR T cells faces substantial challenges, including the dense architecture of the tumour tissue, the tolerogenic environment with low tumour-intrinsic immunogenicity, the rareness of targetable tumour-selective antigens, the antigenic heterogeneity of cancer cells, and the profound metabolic and immune cell disbalances. This Review provides an overview of CAR T cell trials in the treatment of gastrointestinal cancers, discussing considerations relating to safety, efficacy, potential reasons for failure and options for improving CAR T cells for the future. In addition, lessons regarding how to improve efficacy are drawn from CAR T cells armed with adjuvants that sustain their activation within the hostile environment and activate resident immune cells. As the field is rapidly evolving, current treatment modalities and editing CAR T cell functionalities are being refined towards a potentially more successful CAR T cell therapy for gastrointestinal cancers.
尽管有多种治疗选择，但大多数胃肠道癌症的死亡率仍然很高，对免疫疗法的反应也很差。嵌合抗原受体（CAR）工程化T细胞在治疗血液系统恶性肿瘤方面取得了前所未有的疗效，这引发了人们将CAR-T细胞疗法应用于胃肠道癌症治疗的兴趣。用传统的CAR-T细胞治疗实体癌面临着巨大挑战，包括肿瘤组织的致密结构、肿瘤内在免疫原性低的致耐受性环境、可靶向的肿瘤选择性抗原的稀缺性、癌细胞的抗原异质性，以及严重的代谢和免疫细胞失衡。本综述概述了CAR-T细胞治疗胃肠道癌症的试验，讨论了与安全性、疗效、失败的潜在原因以及未来改进CAR-T细胞的选择相关的考虑因素。此外，还从携带佐剂的CAR-T细胞中吸取了有关如何提高疗效的经验教训，这些佐剂可在恶劣环境中维持其激活并激活驻留免疫细胞。随着该领域的迅速发展，目前的治疗方式和编辑CAR-T细胞功能正在朝着可能更成功的胃肠道癌症CAR-T细胞疗法发展。
