Engineered cell-based therapies in ex vivo ready-made CellDex capsules have therapeutic efficacy in solid tumors.

Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. In this study, we created a wide variety of engineered therapeutic cells (ThC) loaded in micropore-forming gelatin methacryloyl (GelMA) hydrogel (CellDex) capsules that can be cultured in vitro prior to their transplantation in surgically debulked solid tumors. We show that both allogeneic and autologous engineered cells, such as stem cells (SCs), macrophages, NK cells, and T cells, proliferate within CellDex capsules and migrate out of the gel in vitro and in vivo. Furthermore, tumor cell specific therapeutic proteins and oncolytic viruses released from CellDex capsules retain and prolong their anti-tumor effects. In vivo, ThCs in pre-manufactured Celldex capsules persist long-term and track tumor cells. Moreover, chimeric antigen receptor (CAR) T cell bearing CellDex (T-CellDex) and human SC releasing therapeutic proteins (hSC-CellDex) capsules show therapeutic efficacy in metastatic and primary brain tumor resection models that mimic standard of care of tumor resection in patients. Overall, this unique approach of pre-manufactured micropore-forming CellDex capsules offers an effective off-the-shelf clinically viable strategy to treat solid tumors locally.

基于封装细胞的实体瘤疗法在临床前研究中已显示出有前景的结果。然而，在移植前无法培养封装的治疗细胞限制了其向临床应用的转化。在这项研究中，我们制造了多种装载在形成微孔的明胶甲基丙烯酰基（GelMA）水凝胶（CellDex）胶囊中的工程化治疗细胞（ThC），这些胶囊在移植到手术切除后的实体瘤之前可以在体外进行培养。我们发现同种异体和自体工程化细胞，如干细胞（SCs）、巨噬细胞、自然杀伤细胞和T细胞，都能在CellDex胶囊内增殖，并在体外和体内从凝胶中迁移出来。此外，从CellDex胶囊释放的肿瘤细胞特异性治疗蛋白和溶瘤病毒保持并延长了它们的抗肿瘤效果。在体内，预先制造的CellDex胶囊中的治疗细胞长期存在并追踪肿瘤细胞。此外，携带嵌合抗原受体（CAR）T细胞的CellDex（T - CellDex）和释放治疗蛋白的人干细胞（hSC - CellDex）胶囊在模拟患者肿瘤切除标准治疗的转移性和原发性脑肿瘤切除模型中显示出治疗效果。总体而言，这种独特的预先制造形成微孔的CellDex胶囊的方法为局部治疗实体瘤提供了一种有效的现成的临床可行策略。