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.

项目摘要收养细胞疗法（ACT）治疗，其中癌症患者注入自体肿瘤特定的细胞毒性（CD8+）T细胞扩展和激活的离体已逐渐吸引人癌症患者。尽管ACT在黑色素瘤方面表现出了巨大的临床成功，但普遍采用一直是限制，因为ACT依赖于极为复杂的基于细胞的方法，其价格很高。最近，增加了重点已放在增强的细胞平台上，例如人造抗原呈现细胞（AAPC），这表明了以更快，更可调的方式激活肿瘤特异性CD8+ T细胞的希望。而多数 AAPC系统已应用于离体设置，即AAPC的生物相容性材料的开发平台扩大了这些系统将在体内使用的潜力，从而减少了冗长的培养时间和与治疗相关的成本。拟议项目的目的是开发一种新型的生物材料AAPC CD8+ T细胞在体内直接的，抗原特异性激活进行癌症免疫疗法。颗粒平台是由可生物降解和生物相容性聚合物的新型混合物制成，聚（乳酸 - 糖）酸（PLGA）和 poly（beta氨基酯）（PBAE），促进了最佳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，以及对肿瘤负担宿主中体内抗原特异性T细胞激活的洞察力。我们将开发免疫学兼容的颗粒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的物理化学特性，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，我们将重点放在合并细胞因子，其他信号上在T细胞激活，局部和持续的方式中很重要。我们将研究各种细胞因子，例如IL-2，IL-15和IL-21，可能在产生效应子和记忆T细胞中发挥作用。在一起，我们将确定在体外针对鼠和人类T细胞激活进行优化的领先三信号AAPC。最后，我们将在体内应用领先的AAPC，分析其CD8+ T细胞的激活，膨胀和抗 - 肿瘤能力。如果成功，该建议将产生一种新型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免疫疗法和减少健康差异。