Kim Jihoon, Francis David M, Thomas Susan N
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA.
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA.
Nanomaterials (Basel). 2021 Feb 12;11(2):471. doi: 10.3390/nano11020471.
The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8 T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.
通过使用功能阻断抗体对免疫检查点进行治疗性抑制，包括细胞毒性T淋巴细胞相关蛋白（CTLA）-4和程序性细胞死亡蛋白1（PD-1），可以通过增强CD8 T细胞介导的抗癌免疫来改善临床结果。然而，患者反应率低和免疫相关不良事件发生率高仍然是扩大这类被称为免疫检查点阻断（ICB）治疗益处的重大挑战。为了克服这些重大限制，可控递送和释放策略为此类治疗提供了独特优势，这类治疗通常通过全身给药（如静脉注射），但最近研究表明，通过局部给药途径也具有高效性。因此，在本文中，我们描述了一种用于从肿瘤部位附近的局部注射中持续释放阻断CTLA-4和PD-1信号抗体的交联水凝胶。与使用等效注射途径推注游离抗体相比，该制剂具有高效且持久的抗癌效果，同时全身毒性降低。因此，该制剂和策略代表了一种在ICB癌症免疫治疗中实现抗体高效安全递送的方法。
