An Engineered Nanocarrier Platform for Enhancing Immune Responses to Neoantigen-Targeted Cancer Vaccines

用于增强新抗原靶向癌症疫苗免疫反应的工程纳米载体平台

• 批准号: 10560602
• 负责人: Jessalyn J Baljon
• 金额: $ 2.7万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2023-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560602
• 关键词: Adjuvant; Agonist; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Vaccines; Cellular Immunity; Charge; Clinical; Colon Carcinoma; Cross Presentation; Dendritic Cells; Development; Dinucleoside Phosphates; Disadvantaged; Drug Delivery Systems; Educational Status; Endosomes; Engineering; Ensure; Goals; Histocompatibility Antigens Class I; Hydrophobicity; Immune response; Immunity; Immunology; In Vitro; Innate Immune Response; Length; Lipids; Lymphatic; MC38; Malignant Neoplasms; Measures; Mentors; Methods; Minority; Modeling; Mus; Nanotechnology; Patients; Peptide Vaccines; Peptides; Periodicity; Polymers; Property; Research; Resistance; STING agonists; System; T cell response; T-Cell Activation; T-Lymphocyte; TLR4 gene; TLR7 gene; TLR9 gene; Tail; Technology; Toll-like receptors; Training; Treatment Efficacy; Tumor Antigens; Vaccination; Vaccine Adjuvant; Vaccines; antigen-specific T cells; cancer therapy; career; chemical property; design; efficacy testing; immune checkpoint blockade; immunoengineering; immunogenic; immunogenicity; immunoregulation; improved; in vivo; lymph nodes; lymphatic drainage; melanoma; multidisciplinary; nanocarrier; nanoengineering; nanoparticle; nanoparticle delivery; nanopolymer; neoantigens; novel therapeutics; novel vaccines; particle; pharmacologic; response; success; synergism; tumor; tumor growth; uptake; vaccine acceptance; vaccine development; vaccine efficacy; vaccine platform

Project Summary Vaccines targeting cancer neoantigens have the potential to enhance the magnitude, function, and duration of an anti-tumor T cell response, offering a promising strategy to improve response rates to immune checkpoint blockade (ICB). However, neoantigenic peptides are typically poorly immunogenic and even when administered in combination with an adjuvant do not elicit a sufficiently strong anti-tumor T cell response for maximal efficacy. This can be attributed to several factors, including poor lymphatic accumulation, low cellular uptake by antigen presenting cells (APCs), and inefficient cross-presentation to CD8+ T cells. The goal of this research is to design and evaluate a nanoparticle vaccine platform to potentiate cellular immunity against peptide neoantigens. We will do this through the design of nanoparticle vaccine technology that overcomes these drug delivery challenges through several, intertwined, methods: 1) Particles will be designed to allow simultaneous delivery of antigen and adjuvant to the same APC, resulting in coordinated expression of co-stimulatory markers and presentation of antigen, which will enhance downstream T cell activation. 2) Nanoparticles will be engineered with pH- responsive properties that promote cytosolic delivery of the antigen to increase cross presentation on MHC class I molecules, resulting in a stronger CD8+ T cell response. 3) A rapid and facile strategy for loading of peptide antigens will be employed, which will allow patient-specific neoantigenic peptides of diverse chemical properties to be efficiently integrated into the nanoparticle vaccine. 4) Nanoparticle properties will be optimized to allow for delivery of multiple, synergistically-acting adjuvants in order to further enhance T cell responses. We propose to accomplish this through two Specific Aims: 1) We will develop a nanotechnology for co-delivery of STING agonists and patient-specific peptide neoantigens. Peptide and nanoparticle properties will be optimized, the ability of the vaccine to activate an antigen-specific immune response will be assessed in vitro and in vivo, and efficacy will be evaluated using know murine neoantigens. 2) We will investigate adjuvant synergy between STING and toll-like receptor agonists by evaluating their ability to enhance antigen cross-presentation on APCs and induce antigen-specific T cell responses. Synergistic combinations will be co-loaded into the nanoparticle vaccine platform and efficacy will be evaluated in vitro and in vivo. We hypothesize that this new vaccine platform will generate a strong patient-specific, anti-tumor T cell response targeting a diversity of neoantigens, resulting in enhanced responses to ICB. This research will contribute to our growing understanding of how materials can be engineered to modulate immune responses and will result in a versatile new drug delivery technology that has potential to improve personalized cancer vaccines. This proposal also describes a multidisciplinary mentoring and training plan at the intersection of engineering and immunology. This plan has been customized to ensure the success of the project and the applicant by providing high-level training for a research career in the emerging field of immunoengineering.

项目摘要 靶向癌症新抗原的疫苗具有增强肿瘤免疫应答的幅度、功能和持续时间的潜力。 抗肿瘤T细胞反应，为提高免疫检查点的反应率提供了一种有前途的策略 阻断（ICB）。然而，新抗原肽通常是免疫原性差的，并且即使当施用时， 与佐剂组合不能引发足够强抗肿瘤T细胞应答以达到最大功效。 这可以归因于几个因素，包括淋巴积聚不良，抗原的细胞摄取低， 在某些实施方案中，CD 8 + T细胞的交叉递呈效率较低，并且与CD 8 + T细胞的交叉递呈效率较低。这项研究的目的是设计 并评估纳米颗粒疫苗平台以增强针对肽新抗原的细胞免疫。我们 我们将通过设计纳米疫苗技术来克服这些药物输送挑战 通过几种相互交织的方法：1）将颗粒设计成允许同时递送抗原 和佐剂相同的APC，导致协调表达的共刺激标志物和呈递 抗原，这将增强下游T细胞活化。2)纳米颗粒将根据pH值进行设计- 促进抗原的胞质递送以增加MHC类上的交叉呈递的响应特性 I分子，导致更强的CD 8 + T细胞应答。3)一种快速简便的多肽负载策略 将使用抗原，这将允许具有不同化学性质的患者特异性新抗原肽 以有效地整合到纳米颗粒疫苗中。4)纳米颗粒的性能将被优化，以允许 递送多种协同作用的佐剂以进一步增强T细胞应答。我们建议 通过两个具体目标实现这一点：1）我们将开发一种纳米技术，用于共同交付STING 激动剂和患者特异性肽新抗原。肽和纳米颗粒的性质将得到优化， 将在体外和体内评估疫苗激活抗原特异性免疫应答的能力， 将使用已知的鼠新抗原来评价效力。2)我们将研究佐剂之间的协同作用 STING和toll样受体激动剂通过评估其增强抗原在APC上交叉呈递的能力 并诱导抗原特异性T细胞应答。协同组合将被共同加载到纳米颗粒中 将在体外和体内评估疫苗平台和功效。我们假设这个新的疫苗平台 将产生针对多种新抗原的强烈的患者特异性抗肿瘤T细胞应答， 加强对ICB的响应。这项研究将有助于我们不断了解材料如何 将被设计成调节免疫反应，并将导致一种多功能的新药物输送技术， 有潜力改进个性化癌症疫苗。该提案还描述了一个多学科的 工程学和免疫学交叉领域的指导和培训计划。此计划已定制 确保项目和申请人的成功，通过提供高水平的培训，为研究生涯， 新兴的免疫工程领域