Engineered Vaccines for Neoantigen Targeted Cancer Immunotherapy

项目摘要 免疫检查点阻断（ICB）是一种免疫疗法，正在彻底改变癌症治疗，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肿瘤细胞的生长不足。 识别肿瘤的内源性产生的、预先存在的T细胞的数量、多样性和/或功能 新抗原和浸润肿瘤。因此，迫切需要制定新的战略， 新抗原特异性T细胞的数量、广度和质量，以将细胞毒性CD 8 + T细胞募集到肿瘤中，以及 来增强它们的扩张效应子功能和持久性为了实现这一目标，我们提出了一个新的战略， 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），我们已经设计克服几个关键的免疫药理学障碍，限制癌症 疫苗效力STAN-V平台基于聚合物纳米颗粒， 共递送肽新抗原和干扰素基因刺激物（STING）的激动剂， 已经证明刺激有效的新抗原特异性CD 8 + T细胞并增加对ICB的应答。我们 本R 01申请的目的是推进和成熟STAN-V作为新抗原的通用平台， 靶向癌症疫苗。我们将通过以下具体目标来实现这一目标。首先，我们将发展 并优化了一种简单的战略，快速制造STAN-V的基础上自发和有效的加载， 用优化的亲脂性结构域设计的新抗原肽。我们将评估其容量 增加新抗原特异性T细胞对理化性质的应答的幅度和宽度的方法 不同的新抗原因此，我们希望这些研究能够提高STAN-V的战备能力， 个性化疫苗技术。其次，我们将利用STAN的独特形态和性质， vs开发和优化一种基于协同包装和协同递送的新型佐剂组合 STING和TLR激动剂。我们将系统地探索联合佐剂递送对 先天性和适应性免疫，我们预计这些研究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新的方法， 通过接种引发的T细胞归巢和浸润。这一战略将利用系统管理， 纳米颗粒STING激动剂，重塑肿瘤环境，以增强T细胞浸润，增殖， 功能总的来说，这些研究将推进STAN-V作为一种使能和通用的技术，用于刺激 强大的新抗原特异性T细胞应答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.