Department of Bioengineering, University of California, Los Angeles, CA, USA.
California NanoSystems Institute, University of California, Los Angeles, CA, USA.
Nat Biomed Eng. 2021 Sep;5(9):1038-1047. doi: 10.1038/s41551-021-00712-1. Epub 2021 Apr 26.
The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release-through the implantation of a hyaluronic acid hydrogel-of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.
实体瘤的免疫抑制微环境降低了嵌合抗原受体 T 细胞（CAR-T 细胞）的抗肿瘤活性。在这里，我们表明，通过植入透明质酸水凝胶将针对人软骨素硫酸盐蛋白聚糖 4 的 CAR-T 细胞、包封细胞因子白细胞介素 15 的聚合物纳米颗粒和与检查点抑制剂程序性死亡配体 1 结合的血小板递送至切除的皮下黑色素瘤小鼠的肿瘤腔内，可以通过远隔效应抑制肿瘤的局部复发和远处肿瘤的生长。该水凝胶作为储库，有助于增强 CAR-T 细胞在手术床内的分布，炎症微环境触发血小板激活和随后的血小板衍生的微粒释放。通过生物相容性水凝胶储库进行手术后局部联合免疫治疗的递送可能代表了预防具有可切除肿瘤的癌症复发的一种转化途径。
