Engineering injectable T cell stimulating microparticles for cancer immunotherapy

工程可注射 T 细胞刺激微粒用于癌症免疫治疗

• 批准号: 10670677
• 负责人: Natalie Katerina Livingston
• 金额: $ 4.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670677
• 关键词: 3-Dimensional; Adoptive Cell Transfers; Affect; Antibodies; Antigen-Presenting Cells; Antigens; Autologous; Biomimetics; Bypass; CD28 gene; CD44 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CTAG1 gene; Cancer Model; Cell Adhesion Molecules; Cell Culture Techniques; Cell Differentiation process; Cell Separation; Cells; Cellular immunotherapy; Clinical; Collagen; Colon Carcinoma; Complex; Cues; Encapsulated; Engineering; Extracellular Matrix; Financial Hardship; Formulation; Generations; Goals; Human; Human Cell Line; Hyaluronic Acid; Hydrogels; IL7 gene; Immunocompetent; Immunotherapy; In Situ; In Vitro; Injectable; Interleukin-10; Interleukin-15; Interleukin-2; Lead; Ligand Binding; MC38; MEL Gene; Melanoma Cell; Memory; Methods; Modeling; Mus; Particulate; Patients; Peptide/MHC Complex; Phenotype; Plague; Price; Property; Research; Role; Signal Transduction; Source; Standardization; Subcutaneous Injections; System; T cell response; T cell therapy; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Test Result; Testing; Therapeutic Uses; Transgenic Organisms; Treatment Efficacy; Tumor Expansion; anti-cancer; antigen-specific T cells; bioscaffold; cancer immunotherapy; cancer therapy; clinically relevant; cost; cytokine; density; design; efficacy testing; experimental study; improved; in vivo; innovation; insight; interleukin-21; lymph nodes; manufacture; manufacturing cost; melanoma; migration; novel; novel strategies; particle; physical property; response; scaffold; subcutaneous; success; tumor

Project Summary Adoptive T cell therapy (ACT) is a T cell based cancer therapy in which autologous T cells are isolated from the patient, activated and expanded ex vivo, then reinfused into the patient. While ACT has shown great clinical success, the success has been limited to melanoma, and complex manufacturing considerations create a large price tag. Innovations in in scalable, acellular systems for T cell activation, such as artificial antigen presenting cells (aAPCs), has improved the ex vivo expansion of CD8+ T cells by shortening culture times and providing tighter control of the resulting T cell phenotype and function. However, T cell culture with aAPCs still takes several weeks and requires manufacturing labor and cost. Platforms for in vivo activation of antigen-specific T cells would decrease the cost and complexity of T cell therapy. The goal of the proposed project is to create the first biomaterial scaffold for direct, in vivo, antigen-specific activation of CD8+ T cells for cancer immunotherapy. The platform, termed the artificial lymph node (aLN), is a hyaluronic acid hydrogel conjugated with signals 1 (peptide-MHC), 2 (anti-CD28) and 3 (cytokine support) that can be injected subcutaneously to create a T cell activating microenvironment. We will investigate the effects of 3D scaffold parameters on T cell activation as well as gain insight into the dynamics of in vivo antigen- specific T cell activation in an immune competent host. We will develop injectable aLN microparticles (MPs) that will compact in vivo to form a T cell activating scaffold. We will first investigate physical properties of the aLN MPs such as signal density, stiffness, and size. We will also investigate the addition of cell adhesion proteins to facilitate migration of the T cells within the scaffold. Second, we will incorporate a local and sustained signal 3 (cytokine) signaling component. We will test a variety of cytokines, including IL-2, IL-7, IL-15, and IL-21, for their ability to generate both effector and memory cells. With the lead cytokine cocktail, we will test two methods of integration, antibody presentation and encapsulation. These aLN parameters will be optimized for both murine and human antigen- specific T cell expansion. Finally, we will test the efficacy of the aLN MPs for in vivo activation and expansion of CD8+ T cells and their anti-cancer efficacy, using B16-OVA, B16-SIY, and MC38-OVA for mouse T cells, and the human SK-MEL-37 (A2+/NY-ESO-1+) melanoma cell line for human T cells. If successful, this proposal will produce a novel acellular approach for the in situ generation of an antigen-specific T cell response, expanding the access of immunotherapy to more patients.

项目摘要 收养T细胞疗法（ACT）是一种基于T细胞的癌症治疗，自体T 细胞与患者分离，激活和扩张后体内，然后重新融入 病人。虽然ACT已显示出巨大的临床成功，但成功仅限于 黑色素瘤和复杂的制造考虑因素创造了巨大的价格。创新 用于T细胞激活的可扩展的细胞系统，例如人工抗原呈现细胞 （AAPC），通过缩短培养时间和 提供对所得T细胞表型和功能的更严格控制。但是，T细胞培养 AAPC仍然需要数周的时间，需要制造劳动力和成本。 in 抗原特异性T细胞的体内激活将降低T细胞的成本和复杂性 治疗。拟议项目的目的是创建直接的第一个生物材料脚手架 体内，CD8+ T细胞的抗原特异性激活用于癌症免疫疗法。平台， 称为人造淋巴结（ALN），是一种与信号1的透明质酸水凝胶 （肽-MHC），2（抗CD28）和3（细胞因子支持），可以皮下注射到 创建一个T细胞激活微环境。我们将研究3D支架的影响 T细胞激活的参数，并深入了解体内抗原的动力学 免疫胜任宿主中的特定T细胞激活。 我们将开发可注射的ALN微粒（MPS），该微粒将在体内紧凑以形成T 细胞激活支架。我们将首先研究ALN MP的物理特性，例如 信号密度，刚度和大小。我们还将研究细胞粘附蛋白的添加 促进脚手架内T细胞的迁移。其次，我们将合并本地 持续信号3（细胞因子）信号传导分量。我们将测试各种细胞因子，包括 IL-2，IL-7，IL-15和IL-21同时产生效应子和记忆细胞的能力。与 铅细胞因子鸡尾酒，我们将测试两种整合方法，抗体表现和 封装。这些ALN参数将针对鼠和人类抗原优化 特定的T细胞扩展。最后，我们将测试ALN MPS体内激活的功效 使用B16-OVA，B16-SIY和 小鼠T细胞的MC38-OVA和人类SK-MEL-37（A2+/NY-ESO-1+）黑色素瘤细胞 人类T细胞的线。如果成功，该建议将为 原位生成抗原特异性T细胞反应，扩大了访问的访问 对更多患者进行免疫疗法。