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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要免疫检查点阻断 (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，这在很大程度上可以归因于治疗不足识别肿瘤的内源性、预先存在的 T 细胞的数量、多样性和/或功能新抗原并浸润肿瘤。因此，迫切需要新的战略来支持新抗原特异性 T 细胞的数量、广度和质量，以将细胞毒性 CD8+ T 细胞招募到肿瘤中，以及放大它们的扩张、效应器功能和持久性。为了实现这一目标，我们提出了一项新战略新抗原靶向癌症免疫疗法。我们的方法利用了 STING 激活纳米颗粒疫苗 (STAN-V)，我们设计它是为了克服限制癌症的几个关键的免疫药理学障碍疫苗功效。 STAN-V 平台基于聚合物纳米粒子，旨在增强细胞内肽新抗原和干扰素基因刺激剂激动剂（STING）的共同递送，我们的设计已证明可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 R01 应用的目标是推进 STAN-V 并使其成熟，作为新抗原的通用平台有针对性的癌症疫苗。我们将通过以下具体目标来实现这一目标。首先，我们将开发并优化基于自发和有效负载的 STAN-V 快速制造的简便策略具有优化亲脂性结构域的新抗原肽。我们将评估该设备的容量增加新抗原特异性 T 细胞对物理化学反应的程度和广度的方法多种新抗原。因此，我们期望这些研究能够促进 STAN-V 的转化准备个性化疫苗技术。其次，我们将利用 STAN- 的独特形态和特性 VS 开发和优化基于协调共同包装和共同交付的新型佐剂组合 STING 和 TLR 激动剂。我们将系统地探讨组合佐剂递送对先天性和适应性免疫，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 T 细胞的归巢和浸润。该战略将利用系统管理纳米颗粒 STING 激动剂可重塑肿瘤环境，增强 T 细胞浸润、增殖和功能。总体而言，这些研究将推动 STAN-V 作为一种用于刺激的启用和多功能技术强大的新抗原特异性 T 细胞反应并改善许多癌症的免疫治疗结果。