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

项目摘要 针对癌症新抗原的疫苗有可能增强其大小、功能和持续时间 一种抗肿瘤T细胞反应，为提高免疫检查点的应答率提供了一种有前途的策略 封锁(ICB)。然而，新的抗原肽通常免疫原性很差，即使在给药时也是如此。 与佐剂联合使用不会引起足够强的抗肿瘤T细胞反应以达到最大疗效。 这可以归因于几个因素，包括淋巴聚集不良，细胞对抗原的摄取率低。 提呈细胞(APC)，以及对CD8T细胞的低效交叉提呈。这项研究的目标是设计 并评估了一种纳米颗粒疫苗平台，以增强对肽新抗原的细胞免疫。我们 将通过设计纳米颗粒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)颗粒将被设计成允许同时传递抗原 和佐剂相同的APC，导致协同刺激标记和呈现的协调表达 抗原，这将增强下游T细胞的激活。2)纳米颗粒将被设计成具有pH- 促进胞浆递送抗原以增加MHC类交叉呈递的反应特性 I分子，导致更强的CD8 T细胞反应。3)一种快速、简便的多肽装载策略 将使用抗原，这将允许患者特定的新抗原肽具有不同的化学性质 有效地整合到纳米颗粒疫苗中。4)纳米粒子的性能将得到优化，以允许 提供多种协同作用的佐剂，以进一步增强T细胞反应。我们建议 通过两个具体目标来实现这一点：1)我们将开发一种纳米技术，用于联合传递STING 激动剂和患者特异性多肽新抗原。多肽和纳米颗粒的性能将得到优化， 疫苗激活抗原特异性免疫反应的能力将在体外和体内进行评估，以及 疗效将使用已知的小鼠新抗原进行评估。2)我们将研究佐剂的协同作用 刺痛和Toll样受体激动剂增强抗原在APC上交叉递呈的能力 并诱导抗原特异性T细胞反应。协同作用的组合将被共同加载到纳米颗粒中 疫苗平台和效力将在体外和体内进行评估。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细胞反应，从而 加强对ICB的反应。这项研究将有助于我们加深对材料如何 被设计成调节免疫反应，并将产生一种多功能的新药递送技术， 具有改进个性化癌症疫苗的潜力。这份提案还描述了一种多学科的 在工程学和免疫学的交叉点进行指导和培训计划。此计划已定制 通过为研究生涯提供高水平的培训，确保项目和申请者的成功 免疫工程的新兴领域。

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.