Engineered Vaccines for Neoantigen Targeted Cancer Immunotherapy

用于新抗原靶向癌症免疫治疗的工程疫苗

• 批准号: 10652625
• 负责人: John Tanner Wilson
• 金额: $ 55.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652625
• 关键词: Address; Adjuvant; Agonist; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Maturation; Cellular Immunity; Characteristics; Charge; Circulation; Clinical; Clinical Treatment; Data; Dendritic Cells; Development; Dinucleoside Phosphates; Drug Delivery Systems; Endosomes; Engineering; Formulation; Goals; Homing; Hydrophobicity; Immune response; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Inflammatory Response; Interferon Type I; Investigation; Length; Libraries; Link; Lipids; Malignant Neoplasms; Mediating; Minority; Modeling; Morphology; Mutation; Myeloid Cells; N-terminal; Natural Immunity; Patients; Peptides; Periodicity; Pharmacologic Substance; Polymers; Proliferating; Property; Publishing; Readiness; Regimen; Research; Resistance; Science; Shapes; Signal Transduction; Solid Neoplasm; Stimulator of Interferon Genes; T cell infiltration; T cell response; T-Cell Activation; T-Lymphocyte; TLR4 gene; Technology; Testing; Tumor Immunity; Vaccination; Vaccine Adjuvant; Vaccine Therapy; Vaccines; Vesicle; adaptive immunity; antigen-specific T cells; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; clinical translation; combinatorial; cytotoxic; cytotoxic CD8 T cells; design; fabrication; immune checkpoint blockade; immunoengineering; immunogenicity; improved; improved outcome; insight; lipophilicity; lymph nodes; manufacture; multidisciplinary; nano; nanoparticle; nanopolymer; nanoscale; neoantigen vaccine; neoantigens; novel; novel strategies; novel therapeutics; particle; personalized immunotherapy; pharmacologic; protein aminoacid sequence; recruit; response; success; synchronous delivery; synergism; therapeutic vaccine; therapy outcome; treatment response; tumor; tumor immunology; tumor microenvironment; vaccine delivery; vaccine efficacy; vaccine platform; virtual; Address; Adjuvant; Agonist; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Maturation; Cellular Immunity; Characteristics; Charge; Circulation; Clinical; Clinical Treatment; Data; Dendritic Cells; Development; Dinucleoside Phosphates; Drug Delivery Systems; Endosomes; Engineering; Formulation; Goals; Homing; Hydrophobicity; Immune response; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Inflammatory Response; Interferon Type I; Investigation; Length; Libraries; Link; Lipids; Malignant Neoplasms; Mediating; Minority; Modeling; Morphology; Mutation; Myeloid Cells; N-terminal; Natural Immunity; Patients; Peptides; Periodicity; Pharmacologic Substance; Polymers; Proliferating; Property; Publishing; Readiness; Regimen; Research; Resistance; Science; Shapes; Signal Transduction; Solid Neoplasm; Stimulator of Interferon Genes; T cell infiltration; T cell response; T-Cell Activation; T-Lymphocyte; TLR4 gene; Technology; Testing; Tumor Immunity; Vaccination; Vaccine Adjuvant; Vaccine Therapy; Vaccines; Vesicle; adaptive immunity; antigen-specific T cells; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; clinical translation; combinatorial; cytotoxic; cytotoxic CD8 T cells; design; fabrication; immune checkpoint blockade; immunoengineering; immunogenicity; improved; improved outcome; insight; lipophilicity; lymph nodes; manufacture; multidisciplinary; nano; nanoparticle; nanopolymer; nanoscale; neoantigen vaccine; neoantigens; novel; novel strategies; novel therapeutics; particle; personalized immunotherapy; pharmacologic; protein aminoacid sequence; recruit; response; success; synchronous delivery; synergism; therapeutic vaccine; therapy outcome; treatment response; tumor; tumor immunology; tumor microenvironment; vaccine delivery; vaccine efficacy; vaccine platform; virtual

PROJECT SUMMARY Immune checkpoint blockade (ICB) is an immunotherapy that is revolutionizing cancer treatment, but is effective in a minority of patients. Across many solid tumor types, this can largely be ascribed to an insufficient number, diversity, and/or function of endogenously generated, pre-existing T cells that recognize tumor neoantigens and infiltrate tumors. Therefore, there is a critical need for new strategies to bolster the magnitude, breadth, and quality of neoantigen-specific T cells, to recruit cytotoxic CD8+ T cells to tumors, and to amplify their expansion, effector function, and persistence. Towards this goal, we propose a new strategy for neoantigen-targeted cancer immunotherapy. Our approach leverages a STING-activating nanoparticle vaccine (STAN-V) that we have designed to overcome several critical immunopharmacological barriers that limit cancer vaccine efficacy. The STAN-V platform is based on polymer nanoparticles engineered to enhance intracellular co-delivery of peptide neoantigen and agonists of stimulator of interferon genes (STING), a design that we have demonstrated stimulates potent neoantigen-specific CD8+ T cells and increases response to ICB. Our objective in this R01 application is to advance and mature STAN-V as a universal platform for neoantigen- targeted cancer vaccines. We will accomplish this through the following Specific Aims. First, we will develop and optimize a facile strategy for rapid fabrication of STAN-Vs based on spontaneous and efficient loading of neoantigenic peptides designed with optimized lipophilic domains. We will evaluate the capacity of this approach to increase the magnitude and breadth of neoantigen-specific T cell responses to physicochemically diverse neoantigens. As such, we expect these studies to advance the translational-readiness of STAN-Vs as a personalized vaccine technology. Second, we will leverage the unique morphology and properties of STAN- Vs to develop and optimize a novel adjuvant combination based on coordinated co-packaging and co-delivery of STING and TLR agonists. We will systematically explore the effect of combinatorial adjuvant delivery on innate and adaptive immunity, studies that we expect will yield an optimized adjuvant combination for stimulating antitumor cellular immunity. Third, we will devise and test a new approach for enhancing tumor homing and infiltration of T cells elicited via vaccination. This strategy will leverage systemic administration of a nanoparticle STING agonist that reshapes the tumor milieu to enhance T cell infiltration, proliferation, and function. Overall, these studies will advance STAN-Vs as an enabling and versatile technology for stimulating robust neoantigen-specific T cell responses and improving outcomes of immunotherapy across many cancers.

项目摘要 免疫检查点封锁（ICB）是一种正在彻底改变癌症治疗的免疫疗法，但 对少数患者有效。在许多实体瘤类型中，这很大程度上可能归因于不足 识别肿瘤的内生产生的预先存在的T细胞的数量，多样性和/或功能 新抗原和浸润肿瘤。因此，迫切需要新策略来加强 新抗原特异性T细胞的大小，广度和质量，将细胞毒性CD8+ T细胞募集到肿瘤中，并且 放大它们的扩展，效应子功能和持久性。为了实现这一目标，我们提出了一种新的策略 新抗原靶向的癌症免疫疗法。我们的方法利用刺激性纳米颗粒疫苗 （Stan-V）我们旨在克服限制癌症的几个关键免疫药物障碍 疫苗功效。 Stan-V平台基于设计用于增强细胞内的聚合物纳米颗粒 肽新抗原和干扰素基因刺激剂（Sting）的激动剂的共同传递，这是我们的设计 已经显示出刺激有效的新抗原特异性CD8+ T细胞，并增加对ICB的反应。我们的 此R01应用中的目的是推进和成熟的stan-V作为新抗原的通用平台 - 靶向癌症疫苗。我们将通过以下特定目标来实现这一目标。首先，我们将发展 并优化一种基于自发有效的负载来快速制造Stan-Vs的便利策略 设计具有优化的亲脂域的新抗原肽。我们将评估这一能力 增加新抗原特异性T细胞对物理化学的幅度和广度的方法 多样的新抗原。因此，我们希望这些研究能够将Stan-Vs的翻译准备程度提高为 一种个性化的疫苗技术。其次，我们将利用stan-的独特形态和特性 Vs以协调的共包装和共同交付的方式开发和优化一种新型的佐剂组合 Sting和TLR激动剂。我们将系统地探索组合辅助交付对 天生和适应性免疫，我们期望的研究将产生优化的佐剂组合 刺激抗肿瘤的细胞免疫。第三，我们将设计并测试一种增强肿瘤的新方法 通过疫苗接种引起的T细胞的归位和浸润。该策略将利用系统管理 纳米颗粒刺激激动剂，可重塑肿瘤环境，以增强T细胞浸润，增殖和 功能。总体而言，这些研究将推进STAN-VS，作为一种刺激的有利和多功能技术 强大的新抗原特异性T细胞反应和许多癌症的免疫疗法的预后。