Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University of Lausanne and University Hospital of Lausanne (CHUV), Switzerland.
Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University of Lausanne and University Hospital of Lausanne (CHUV), Switzerland.
Curr Opin Biotechnol. 2020 Oct;65:75-87. doi: 10.1016/j.copbio.2020.01.009. Epub 2020 Feb 25.
Synthetic biology has been transformative to the treatment of advanced hematological malignancies by chimeric antigen receptor (CAR)-engineered T cells. A range of obstacles are now understood to limit the responses of solid epithelial-derived tumors to CAR therapy. For example, inefficient tumor homing and a fortified stroma can restrain the number of CAR-T cells reaching the tumor bed. Upon transendothelial migration across the tumor vasculature, CAR-T cells face a highly suppressive microenvironment that can quickly render them hypofunctional. Safety also remains a critical issue for advancing CAR therapy of solid tumors. Innovative CAR design as well as coengineering and combinatorial treatment strategies with oncolytic adenovirus, radiotherapy, vaccines, chemotherapy, small molecules and monoclonal antibodies hold tremendous potential to support CAR-T cell control of solid tumors, either by directly promoting CAR-T cell function, or/and by re-programming the TME and harnessing the endogenous immune system against the tumor.
合成生物学通过嵌合抗原受体 (CAR) 修饰的 T 细胞改变了晚期血液系统恶性肿瘤的治疗方式。现在已经了解到一系列障碍限制了 CAR 疗法对实体上皮源性肿瘤的反应。例如，肿瘤归巢效率低下和强化的基质可以限制到达肿瘤床的 CAR-T 细胞数量。CAR-T 细胞在穿过肿瘤血管内皮细胞迁移后，面临着高度抑制性的微环境，这可能使其很快功能低下。对于推进实体瘤的 CAR 治疗，安全性仍然是一个关键问题。创新的 CAR 设计以及与溶瘤腺病毒、放疗、疫苗、化疗、小分子和单克隆抗体的联合工程和组合治疗策略，通过直接促进 CAR-T 细胞功能，或者/和重新编程 TME 并利用内源性免疫系统对抗肿瘤，为 CAR-T 细胞控制实体瘤提供了巨大的潜力。
