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

基本信息

批准号：
10537258
负责人：
Natalie Katerina Livingston
金额：
$ 4.68万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10537258
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 Cells Cellular immunotherapy Clinical Collagen Colon Carcinoma Complex Cues Cytokine Signaling 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 Signal Sequences 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 Time Transgenic Organisms Treatment Efficacy Tumor Expansion anti-cancer antigen-specific T cells base bioscaffold cancer cell cancer immunotherapy cancer therapy clinically relevant cost cytokine density design efficacy testing experimental study improved in vivo innovation insight lymph nodes melanoma migration novel novel strategies physical property response scaffold subcutaneous success tumor

项目摘要

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.

项目概要过继性 T 细胞疗法 (ACT) 是一种基于 T 细胞的癌症疗法，其中自体 T 细胞从患者体内分离出来，离体激活并扩增，然后重新注入体内病人。虽然 ACT 在临床上取得了巨大的成功，但其成功仅限于黑色素瘤和复杂的制造考虑因素导致了高昂的价格标签。创新于用于 T 细胞激活的可扩展的非细胞系统，例如人工抗原呈递细胞 (aAPCs)，通过缩短培养时间和改善 CD8+ T 细胞的离体扩增提供对所产生的 T 细胞表型和功能的更严格控制。然而，T 细胞培养制造装甲运兵车仍然需要几周的时间，并且需要制造劳动力和成本。平台用于抗原特异性 T 细胞的体内激活将降低 T 细胞的成本和复杂性治疗。该项目的目标是创建第一个直接用于生物材料支架体内抗原特异性激活 CD8+ T 细胞用于癌症免疫治疗。该平台，称为人工淋巴结 (aLN)，是一种与信号 1 结合的透明质酸水凝胶（肽-MHC）、2（抗 CD28）和 3（细胞因子支持）可皮下注射至创造T细胞激活微环境。我们将研究3D脚手架的效果 T 细胞激活的参数，并深入了解体内抗原的动态具有免疫能力的宿主中的特异性 T 细胞激活。我们将开发可注射的 aLN 微粒 (MP)，它会在体内压缩形成 T 细胞活化支架。我们将首先研究 aLN MP 的物理特性，例如信号密度、刚度和尺寸。我们还将研究细胞粘附蛋白的添加促进T细胞在支架内的迁移。其次，我们将结合本地和持续信号 3（细胞因子）信号成分。我们将测试多种细胞因子，包括 IL-2、IL-7、IL-15 和 IL-21，因为它们能够产生效应细胞和记忆细胞。随着主要细胞因子鸡尾酒，我们将测试两种整合方法，抗体呈递和封装。这些 aLN 参数将针对鼠类和人类抗原进行优化特异性 T 细胞扩增。最后，我们将测试 aLN MPs 体内激活的功效使用 B16-OVA、B16-SIY 和 CD8+ T 细胞的扩增及其抗癌功效用于小鼠 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 细胞系。如果成功，该提案将为原位产生抗原特异性 T 细胞反应，扩大了免疫疗法惠及更多患者。