Engineered Vaccines for Neoantigen Targeted Cancer Immunotherapy

项目总结 免疫检查点阻断(ICB)是一种正在给癌症治疗带来革命性变化的免疫疗法，但 对少数患者有效。在许多实体肿瘤类型中，这在很大程度上可以归因于 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 新抗原和浸润性肿瘤。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 以增强其扩张性、效应器功能和持久性。为了实现这一目标，我们提出了一项新的战略 新抗原靶向癌症免疫疗法。我们的方法利用了一种能激活叮咬的纳米颗粒疫苗 (STAN-V)，我们已经设计了克服几个限制癌症的关键免疫药理障碍 疫苗的效力。Stan-V平台基于聚合物纳米颗粒，旨在增强细胞内 多肽新抗原和干扰素基因刺激物激动剂(STING)的联合传递，这是我们的设计 已经证明能刺激强大的新抗原特异性CD8+T细胞，并增强对ICB的反应。我们的 本R01的应用目的是促进和成熟Stan-V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实现这一目标。首先，我们将发展 并优化了一种基于自发和有效加载的Stan-VS快速制造的简便策略 设计了具有优化的亲脂结构域的新抗原肽。我们将评估这一能力 增加新抗原特异性T细胞对物理化学反应的幅度和广度的方法 不同的新抗原。因此，我们希望这些研究将促进Stan-V AS的翻译准备 一种个性化疫苗技术。第二，我们将利用斯坦独特的形态和特性- VS开发和优化一种基于协同共包装和协同递送的新型佐剂组合 刺痛和TLR激动剂。我们将系统地探索联合佐剂给药的效果。 先天免疫和获得性免疫，我们预计将产生一种优化的佐剂组合 刺激抗肿瘤细胞免疫。第三，我们将设计和测试一种增强肿瘤的新方法。 疫苗接种可引起T细胞归巢和浸润。这一战略将利用系统管理 纳米颗粒刺激剂，重塑肿瘤环境，增强T细胞的渗透，增殖，和 功能。总体而言，这些研究将推动Stan-V成为一种使能和多功能的刺激技术 强大的新抗原特异性T细胞反应和改善许多癌症的免疫治疗结果。

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.