Tri-Signal Artificial Antigen Presenting Cells for Cancer Immunotherapy

项目摘要 免疫细胞疗法（ACT）治疗，其中癌症患者输注自体肿瘤- 特异性细胞毒性（CD 8+）T细胞的体外扩增和活化，已经逐渐变得更有吸引力， 癌症患者。虽然ACT在治疗黑色素瘤方面取得了巨大的临床成功，但普遍采用的情况仍然存在。 然而，由于ACT依赖于极其复杂的基于细胞的方法，并且价格昂贵，因此它是有限的。最近，增加 重点放在增强非细胞平台，如人工抗原呈递细胞（aAPC）， 这显示出以更快、更可调的方式激活肿瘤特异性CD 8 + T细胞的前景。虽然大多数 的aAPC系统已应用于离体设置，用于aAPC的生物相容性材料的开发 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， 和治疗相关的费用。该项目的目标是开发一种新型生物材料aAPC， 直接、抗原特异性激活体内CD 8 + T细胞用于癌症免疫治疗。微粒平台是 由生物可降解和生物相容性聚合物的新型混合物制成，聚（乳酸-乙醇酸）（PLGA）和 聚（β氨基酯）（PBAE），促进包含最佳T细胞活化所需的三种信号 和扩张。我们将研究生物材料特性和信号掺入对体外T细胞的影响， 活化，以及深入了解肿瘤负荷宿主中的体内抗原特异性T细胞活化。 我们将开发免疫相容的，颗粒状的PLGA/PBAE aAPCs用于体内注射和T 细胞激活首先，我们将研究这些aAPC的理化性质，包括生物材料， 组成、大小和表面蛋白质密度。我们将在增强的背景下优化这些属性， CD 8 + T细胞活化和生物学功能。第二，我们将集中于整合细胞因子，额外的信号， 在局部和持续的T细胞活化中起重要作用。我们将研究各种细胞因子， 如IL-2、IL-15和IL-21，其可在产生效应和记忆T细胞中起作用。综合起来看， 我们将鉴定在体外对鼠和人T细胞活化进行优化的主要三信号aAPC。 最后，我们将在体内应用我们领先的aAPC，分析其CD 8 + T细胞活化、扩增和抗-CD 8 + T细胞的能力。 肿瘤能力。如果成功的话，这项提议将产生一种新的仿生方法， 抗原特异性CD 8 + T细胞应答，具有扩大患者接触癌症的潜力 免疫疗法和减少健康差距。

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.