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有可能提高大小，功能和持续时间 抗肿瘤T细胞反应，提供了提高免疫检查点反应率的有希望的策略 封锁（ICB）。然而，新抗原肽的免疫原性通常是不良的，即使给药 与佐剂结合使用，不会引起足够强大的抗肿瘤T细胞反应以达到最大功效。 这可以归因于几个因素，包括淋巴积累不良，抗原的细胞摄取低。 呈现细胞（APC），对CD8+ T细胞效率低下。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 将通过纳米颗粒疫苗技术的设计来实现这一目标，从而克服这些药物的挑战 通过几种相互交织的方法：1）将设计颗粒以同时递送抗原 并佐剂对同一APC，导致共同刺激标记和表现的协调表达 抗原，它将增强下游T细胞激活。 2）纳米颗粒将通过pH-设计 促进抗原的胞质递送以增加MHC类上的交叉表现的响应性能 I分子，导致CD8+ T细胞反应更强。 3）加载肽的快速而轻松的策略 将采用抗原，这将允许患者特异性的新抗原肽的各种化学性质 有效整合到纳米颗粒疫苗中。 4）将优化纳米颗粒性能以允许 为了进一步增强T细胞反应，多种，协同作用的佐剂的递送。我们建议 通过两个具体的目标来实现这一点：1）我们将开发一种纳米技术来共同交付的刺激 激动剂和患者特异性肽新抗原。将优化肽和纳米颗粒特性， 疫苗激活抗原特异性免疫反应的能力将在体外和体内评估，并且 将使用知识鼠新抗原评估功效。 2）我们将研究辅助协同作用 通过评估其增强APC抗原交叉呈递的能力，通过评估其刺激和类似收费的受体激动剂 并诱导抗原特异性T细胞反应。协同组合将共同加载到纳米颗粒中 疫苗平台和功效将在体外和体内评估。我们假设这个新的疫苗平台 将产生针对新抗原多样性的强大患者特异性，抗肿瘤T细胞反应，从而 在增强对ICB的反应中。这项研究将有助于我们对材料如何如何的越来越多的理解 设计以调节免疫反应，并将导致一种多功能的新药物输送技术 有可能改善个性化癌症疫苗。该建议还描述了一个多学科 工程与免疫学交集的指导和培训计划。该计划已被定制 通过为研究事业提供高级培训，以确保项目的成功和申请人 免疫工程的新兴领域。