Tri-Signal Artificial Antigen Presenting Cells for Cancer Immunotherapy

项目总结 过继细胞疗法(ACT)，癌症患者被注入自体肿瘤- 特异性细胞毒(CD8+)T细胞体外扩增和激活，已逐渐变得更具吸引力 癌症患者。尽管ACT在治疗黑色素瘤方面取得了巨大的临床成功，但普遍采用 有限，因为ACT依赖于极其复杂的基于细胞的方法，价格昂贵。最近，增加了 重点是加强非细胞平台，如人工抗原提呈细胞(AAPC)， 这显示出以一种更快、更可调的方式激活肿瘤特异性CD8+T细胞的前景。虽然大多数人 AAPC系统已在体外环境中应用，开发用于AAPC的生物相容性材料 平台已经扩大了这些系统在体内使用的潜力，减少了漫长的培养时间 以及与治疗相关的费用。该项目的目标是开发一种新型生物材料AAPC，用于 体内CD8+T细胞抗原特异性的直接激活，用于癌症免疫治疗。颗粒物平台是 由可生物降解和生物相容的新型聚合物，聚(乳酸-羟基乙酸)酸(PLGA)和 聚(β氨基酯)(PBAE)，促进包含最佳T细胞激活所需的三种信号 和扩张。我们将研究生物材料的特性和信号掺入对体外T细胞的影响 激活，以及深入了解体内抗原特异性T细胞在荷瘤宿主中的激活。 我们将开发免疫兼容的颗粒状PLGA/PBAE aAPC，用于体内注射和T细胞 细胞激活。首先，我们将研究这些aAPC的物理化学性质，包括生物材料 成分、大小和表面蛋白密度。我们将在增强的环境中优化这些属性 CD8+T细胞的活化和生物学功能。第二，我们将专注于整合细胞因子、额外的信号 以局部和持续的方式在T细胞激活中起重要作用。我们将研究各种细胞因子， 如IL-2、IL-15和IL-21，可能在产生效应性和记忆性T细胞方面发挥作用。加在一起， 我们将确定领先的三信号aAPC，它们在体外对小鼠和人类T细胞激活都是优化的。 最后，我们将在体内应用我们领先的aAPC，分析它们的CD8+T细胞的激活、扩增和抗- 肿瘤容量。如果成功，这项提议将产生一种新的仿生方法来利用最优 抗原特异性CD8+T细胞反应，有可能扩大患者接触癌症的机会 免疫疗法和缩小健康差距。

PROJECT SUMMARY Adoptive cellular therapy (ACT) treatments, in which cancer patients are infused with autologous tumor- specific cytotoxic (CD8+) T cells expanded and activated ex vivo, have become gradually more appealing for cancer patients. Although ACT has shown great clinical success with melanoma, universal adoption has been limited, as ACT relies on extremely complex cell-based methods with a significant price tag. Recently, increased emphasis has been placed on enhancing acellular platforms, such as artificial antigen presenting cells (aAPCs), that show promise in activating tumor-specific CD8+ T cells in a quicker, more tunable manner. While a majority of aAPC systems have been applied in ex vivo settings, the development of biocompatible materials for aAPC platforms have expanded the potential of these systems to be used in vivo, lessening the lengthy culture times and costs associated with therapy. The goal of the proposed project is to develop a novel biomaterial aAPC for direct, antigen-specific activation of CD8+ T cells in vivo for cancer immunotherapy. The particulate platform is made from a novel blend of biodegradable and biocompatible polymers, Poly(lactic-co-glycolic) acid (PLGA) and Poly(beta amino ester) (PBAE), that promotes inclusion of the three signals required for optimal T cell activation and expansion. We will investigate the effects of biomaterial properties and signal incorporation on in vitro T cell activation, as well as gain insight into in vivo antigen-specific T cell activation in a tumor-burdened host. We will develop immunologically compatible, particulate PLGA/PBAE aAPCs for in vivo injection and T cell activation. First, we will investigate physicochemical properties of these aAPCs, including biomaterial composition, size, and surface protein density. We will optimize these properties in the context of enhanced CD8+ T cell activation and biological function. Second, we will focus on incorporating cytokines, additional signals that are important in T cell activation, in a local and sustained manner. We will investigate various cytokines, such as IL-2, IL-15, and IL-21, that may play a role in generating effector and memory T cells. Taken together, we will identify leading tri-signal aAPCs that are optimized for both murine and human T cell activation in vitro. Finally, we will apply our leading aAPCs in vivo, to analyze their CD8+ T cell activation, expansion, and anti- tumor capacities. If successful, this proposal will generate a novel biomimetic approach for harnessing optimal antigen-specific CD8+ T cell responses, with the potential of expanding patient access to cancer immunotherapies and reducing health disparities.