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 过继T细胞治疗(ACT)是一种基于T细胞的癌症治疗方法，其中自体T细胞 从患者体内分离细胞，激活并体外扩增，然后再注入 有耐心的。虽然ACT已显示出巨大的临床成功，但其成功仅限于 黑色素瘤和复杂的制造考虑造成了巨大的价格标签。中的创新 可扩展的非细胞T细胞激活系统，如人工抗原提呈细胞 (AAPC)，通过缩短培养时间和促进CD8+T细胞的体外扩增 更严格地控制由此产生的T细胞表型和功能。然而，T细胞培养 使用aAPC仍然需要几周时间，并且需要制造劳动力和成本。适用于 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 心理治疗。拟议项目的目标是创造第一个生物材料支架，用于在 体内，抗原特异性激活的CD8+T细胞用于癌症免疫治疗。站台， 被称为人工淋巴结(ALN)的是一种透明质酸水凝胶，与信号1结合 (多肽-MHC)，2(抗CD28)和3(细胞因子支持)，可皮下注射到 营造激活T细胞的微环境。我们将研究3D支架的效果 关于T细胞激活的参数以及了解体内抗原的动态- 在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(MPS)，这种微粒将在体内致密形成T 细胞激活支架。我们将首先研究ALN MPS的物理性质，如 信号密度、硬度和大小。我们还将研究细胞黏附蛋白的添加 以促进T细胞在支架内的迁移。第二，我们将合并一个本地和 持续信号3(细胞因子)信号组件。我们将测试各种细胞因子，包括 IL-2、IL-7、IL-15和IL-21，因为它们同时具有产生效应细胞和记忆细胞的能力。与 领先的细胞因子鸡尾酒，我们将测试两种整合方法，抗体呈递和 封装。这些ALN参数将针对小鼠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对体内激活的效果 利用B16-OVA、B16-SIY和B16-SIY扩增CD8+T细胞及其抗癌效果 MC38-OVA对小鼠T细胞和人SK-Mel-37(A2+/NY-ESO-1+)黑色素瘤细胞的作用 人类T细胞的专线。如果成功，这项提议将为 原位产生抗原特异的T细胞反应，扩大进入 给更多的患者提供免疫治疗。