Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL, United States.
J Control Release. 2023 Oct;362:620-630. doi: 10.1016/j.jconrel.2023.09.005. Epub 2023 Sep 12.
Chimeric antigen receptor (CAR) T cell therapy has resulted in positive effects on patients with hematologic malignancy but shows limited efficacy in solid tumor treatments due to insufficient trafficking and tumor infiltration, intensive CAR-T-related toxicities, and antigen escape. In this work, we developed and investigated a biodegradable and biocompatible polymeric toroidal-spiral particle (TSP) as a in vivo cell incubator and delivery device that can be implanted near tumor through a minimally invasive procedure or injected near or into solid tumors by using a biopsy needle. The main matrix structure of the millimeter-sized TSP is made from crosslinking of gelatin methacrylamine (GelMA) and poly (ethylene glycol) diacrylate (PEGDA) with a tunable degradation rate from a few days to months, providing appropriate mechanical properties and sustained release of co-encapsulated drugs and/or stimulation compounds. The toroidal-spiral layer of the particles, presenting an internal void volume for high-capacity cell loading and flexibility of co-encapsulating small and large molecular compounds with individually manipulated release schedules, is filled with collagen and suspended T cells. The TSPs promote cell proliferation, activation, and migration in the tumor micro-environment in a prolonged and sustained manner. In this study, the efficacy of mesothelin (MSLN) CAR-T cells released from the TSPs was tested in preclinical mouse tumor models. Compared to systemic and intratumoral injection, peritumoral delivery of MSLN CAR-T cells using the TSPs resulted in a superior antitumor effect. The TSPs made of FDA approved materials as an in vivo reactor may provide an option for efficiently local delivery of CAR-T cells to solid tumors for higher efficacy and lower toxicity, with a minimally invasive administration procedure.
嵌合抗原受体 (CAR) T 细胞疗法已对血液系统恶性肿瘤患者产生了积极影响，但由于转运和肿瘤浸润不足、密集的 CAR-T 相关毒性和抗原逃逸，其在实体瘤治疗中的疗效有限。在这项工作中，我们开发并研究了一种可生物降解和生物相容的聚合物环形螺旋粒子（TSP）作为体内细胞孵化器和输送装置，可通过微创程序植入肿瘤附近，或使用活检针将其注射到或注射到实体瘤附近或内部。毫米级 TSP 的主要基质结构由明胶甲基丙烯酰胺（GelMA）和聚乙二醇二丙烯酸酯（PEGDA）交联而成，具有从几天到几个月不等的可调降解率，提供适当的机械性能和共包封药物和/或刺激化合物的持续释放。粒子的环形螺旋层具有内部空隙体积，可用于高容量细胞负载，并具有灵活性，可以共包封小分子和大分子化合物，并单独控制其释放时间表，内部填充胶原和悬浮 T 细胞。TSP 以延长和持续的方式促进肿瘤微环境中的细胞增殖、激活和迁移。在这项研究中，测试了从 TSP 中释放的间皮素 (MSLN) CAR-T 细胞的功效在临床前小鼠肿瘤模型中。与系统和肿瘤内注射相比，使用 TSP 进行肿瘤周围递送 MSLN CAR-T 细胞可产生更好的抗肿瘤效果。作为体内反应器的由 FDA 批准的材料制成的 TSP 可能为高效局部递送 CAR-T 细胞到实体瘤提供了一种选择，以实现更高的疗效和更低的毒性，同时采用微创管理程序。
