Tri-Signal Artificial Antigen Presenting Cells for Cancer Immunotherapy

用于癌症免疫治疗的三信号人工抗原呈递细胞

基本信息

批准号：
10751133
负责人：
Sydney Rose Shannon
金额：
$ 4.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751133
关键词：
Acids Adoption Adoptive Cell Transfers Adoptive Transfer Antigen-Presenting Cells Antigens Autologous Biocompatible Materials Biological Biological Process Biomimetics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cancer Patient Cell Communication Cell physiology Cells Clinical Complex Couples Cues Dendritic Cells Development Encapsulated Engineering Esters Formulation Generations Glycolates Goals Human Immunologic Factors Immunologics Immunotherapy In Vitro Incubated Injections Interleukin-12 Interleukin-15 Interleukin-2 Licensing Maintenance Membrane Proteins Memory Methods Modeling Mus Particulate Patients Phenotype Polymers Price Process Property Proteins Reduce health disparities Research Safety Signal Transduction Supporting Cell System T cell differentiation T cell response T cell therapy T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Uses Transgenic Organisms Treatment Efficacy Tumor Burden Tumor Expansion Work antigen-specific T cells biocompatible polymer biodegradable polymer cancer immunotherapy chemokine clinical translation clinically relevant cost cost effective cytokine cytotoxic cytotoxicity density design exhaustion experimental study handicapping condition improved in vivo insight interleukin-21 long term memory manufacturing cost melanoma neoplastic cell novel particle response success tumor

项目摘要

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.

项目概要过继细胞疗法（ACT）治疗，其中癌症患者被注入自体肿瘤 - 特异性细胞毒性 (CD8+) T 细胞在体外扩增和激活，已逐渐变得越来越有吸引力癌症患者。尽管 ACT 在治疗黑色素瘤方面取得了巨大的临床成功，但普遍采用尚未得到广泛应用。有限，因为 ACT 依赖于极其复杂的基于细胞的方法，且价格昂贵。近期增加了重点放在增强非细胞平台，例如人工抗原呈递细胞（aAPC），这有望以更快、更可调的方式激活肿瘤特异性 CD8+ T 细胞。虽然大多数 aAPC系统已应用于离体环境，aAPC生物相容性材料的开发平台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 体内 CD8+ T 细胞的直接抗原特异性激活用于癌症免疫治疗。颗粒平台是由可生物降解和生物相容性聚合物、聚乳酸-乙醇酸 (PLGA) 和聚（β 氨基酯）(PBAE)，促进包含最佳 T 细胞激活所需的三个信号和扩展。我们将研究生物材料特性和信号掺入对体外 T 细胞的影响激活，以及深入了解荷瘤宿主体内抗原特异性 T 细胞的激活。我们将开发免疫相容的颗粒 PLGA/PBAE aAPC，用于体内注射和 T 细胞激活。首先，我们将研究这些 aAPC 的理化特性，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 CD8+ T 细胞激活和生物学功能。其次，我们将重点关注整合细胞因子、其他信号这对于 T 细胞以局部和持续的方式激活很重要。我们将研究各种细胞因子，例如 IL-2、IL-15 和 IL-21，它们可能在产生效应 T 细胞和记忆 T 细胞中发挥作用。综合起来，我们将鉴定针对小鼠和人类 T 细胞体外激活进行优化的领先三信号 aAPC。最后，我们将在体内应用我们领先的 aAPC，分析它们的 CD8+ T 细胞激活、扩增和抗- 肿瘤能力。如果成功，该提案将产生一种新颖的仿生方法来利用最佳抗原特异性 CD8+ T 细胞反应，有可能扩大患者患癌症的机会免疫疗法和减少健康差距。