Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mol Ther. 2020 Apr 8;28(4):1056-1067. doi: 10.1016/j.ymthe.2020.02.008. Epub 2020 Feb 13.
Pre-clinical and clinical studies have shown that engineered tumoricidal neural stem cells (tNSCs) are a promising treatment strategy for the aggressive brain cancer glioblastoma (GBM). Yet, stabilizing human tNSCs within the surgical cavity following GBM resection is a significant challenge. As a critical step toward advancing engineered human NSC therapy for GBM, we used a preclinical variant of the clinically utilized NSC line HB1.F3.CD and mouse models of human GBM resection/recurrence to identify a polymeric scaffold capable of maximizing the transplant, persistence, and tumor kill of NSC therapy for post-surgical GBM. Using kinetic bioluminescence imaging, we found that tNSCs delivered into the mouse surgical cavity wall by direct injection persisted only 3 days. We found that delivery of tNSCs into the cavity on nanofibrous electrospun poly-l-lactic acid scaffolds extended tNSC persistence to 8 days. Modifications to fiber surface coating, diameter, and morphology of the scaffold failed to significantly extend tNSC persistence in the cavity. In contrast, tNSCs delivered into the post-operative cavity on gelatin matrices (GEMs) persisted 8-fold longer as compared to direct injection. GEMs remained permissive to tumor-tropic homing, as tNSCs migrated off the scaffolds and into invasive tumor foci both in vitro and in vivo. To mirror envisioned human brain tumor trials, we engineered tNSCs to express the prodrug/enzyme thymidine kinase (tNSCs) and transplanted the therapeutic cells in the post-operative cavity of mice bearing resected orthotopic patient-derived GBM xenografts. Following administration of the prodrug ganciclovir, residual tumor volumes in mice receiving GEM/tNSCs were reduced by 10-fold at day 35, and median survival was extended from 31 to 46 days. Taken together, these data begin to define design parameters for effective scaffold/tNSC composites and suggest a new approach to maximizing the efficacy of tNSC therapy in human patient trials.
临床前和临床研究表明，工程化的杀瘤神经干细胞（tNSCs）是治疗侵袭性脑癌胶质母细胞瘤（GBM）的一种有前途的治疗策略。然而，在 GBM 切除术后，将人类 tNSCs 稳定在手术腔内是一个重大挑战。作为将工程化人类 NSC 疗法推进到 GBM 治疗的关键步骤，我们使用了一种临床上使用的 NSC 系 HB1.F3.CD 的临床前变体和人类 GBM 切除/复发的小鼠模型，以确定一种聚合物支架，能够最大限度地提高 NSC 疗法在 GBM 术后的移植、持久性和肿瘤杀伤效果。通过动力学生物发光成像，我们发现直接注射到小鼠手术腔壁的 tNSCs 仅能持续 3 天。我们发现，将 tNSCs 递送到纳米纤维电纺聚-l-乳酸支架上的腔中可以将 tNSC 的持久性延长至 8 天。改变纤维表面涂层、支架直径和形态并不能显著延长腔内 tNSC 的持久性。相比之下，与直接注射相比，将 tNSCs 递送到手术后的凝胶基质（GEMs）腔中可以将持久性延长 8 倍。GEMs 仍然允许肿瘤趋向性归巢，因为 tNSCs 从支架上迁移并进入体外和体内侵袭性肿瘤灶。为了模拟设想中的人类脑肿瘤试验，我们将 tNSCs 工程化表达前药/酶胸苷激酶（tNSCs），并将治疗性细胞移植到携带切除的原位患者来源的 GBM 异种移植物的小鼠的手术后腔中。在给予前药更昔洛韦后，接受 GEM/tNSCs 治疗的小鼠的残余肿瘤体积在第 35 天减少了 10 倍，中位生存期从 31 天延长至 46 天。综上所述，这些数据开始为有效的支架/tNSC 复合材料定义设计参数，并为最大限度地提高 tNSC 疗法在人类患者试验中的疗效提供了一种新方法。
