Tumor-directed immunostimulatory nanoparticles for novel 'prime-pull'cancer vaccination

项目摘要 尽管传统的癌症疫苗具有变革性的前景，但自2008年以来， 疫苗特异性系统性T细胞通常不能运输到免疫抑制的“冷”肿瘤。传统疫苗 仅产生淋巴结来源的系统性CD 8 + T细胞的扩增或“致敏”，所述系统性CD 8 + T细胞被训练成 全面寻找和清除特异性靶肿瘤细胞。然而，传统的战略 他们目光短浅，因为他们未能开发出将这些T细胞招募到“冷”肿瘤的方法 微环境（TME），通过建立一个强大的局部免疫抑制屏障驱动 很大程度上是由先天免疫细胞功能失调造成的。我们的策略旨在重新编程功能失调的肿瘤居民 先天性抗原呈递细胞（APC），如树突状细胞（DC）和巨噬细胞，通过驱动局部抗- 肿瘤免疫反应与促炎细胞因子梯度，重塑TME从非炎症 “冷”是指发炎，“热”是指从“初始状态”募集或“拉动”全身性T细胞。在最近的巨蟹座 研究论文（Atukorale等人，2019年）和其他初步数据，我们报告了一种 基于新型免疫刺激性纳米颗粒（免疫NP）的“拉动”策略，由于关键的 工程设计特点。免疫-NP将两种协同免疫激动剂共包封在同一载体上 颗粒，cdGMP，STING途径的激动剂，和MPLA，TLR 4途径的激动剂，以促进细胞增殖。 在靶APC中稳健地产生促炎性I型干扰素β。免疫纳米颗粒可以安全地输送 在全身血液循环中实现肿瘤血管周围的广泛和优先沉积 这些区域富含它们的目标APC。免疫纳米颗粒驱动强大的局部自我放大抗肿瘤 免疫反应，利用否则“耗尽”免疫抑制的局部CD 8 + T细胞作为关键 肿瘤清除的效应物，这表明高度有效的“冷到热”TME重编程。我们的中央 假设是标准淋巴结定向CD 8 + T细胞疫苗“初免”与 肿瘤导向的免疫NP“拉”的一种新的“引物-拉”的方法可以提供关键的缺失环节，有效的 癌症疫苗具体目标1将确定免疫NP拉取在免疫NP方面的最佳功能 设计并与抗PD 1共同治疗。具体目标2将制定一个精确的“prime-pull”耦合计划。 具体目标3将评价有效剂量/时间表“预激-拉动”方案的安全性和毒性。博士 Atukorale的职业目标是建立一个基于纳米材料的癌症免疫工程实验室， 独立调查员她将开发免疫纳米材料工具， 免疫力，特别是在致命癌症的情况下。Atukorale博士强大的职业发展计划包括 重要的新的研究合作，高级咨询委员会，研究报告，学院级 研讨会，并计划随后的赠款提案。她未来的赞助机构将设在这两个 医学和工程学院，与她高度跨学科的研究兴趣直接相关。

PROJECT SUMMARY Despite their transformative promise, traditional cancer vaccines have had poor clinical responses since vaccine-specific systemic T cells often cannot traffic to immunosuppressed “cold” tumors. Traditional vaccines generate only a lymph node-derived augmentation or “prime” of systemic CD8+ T cells that are trained to comprehensively seek and eliminate specific target tumor cells. Traditional strategies, however, have been short-sighted in that they have failed to develop methods to recruit these T cells to the “cold” tumor microenvironment (TME) that advances by building a formidable local immunosuppressive barrier driven largely by dysfunctional innate immune cells. Our strategy seeks to reprogram dysfunctional tumor-resident innate antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, by driving a local anti- tumor immune response with a proinflammatory cytokine gradient that reshapes the TME from non-inflamed and “cold” to inflamed and “hot” to recruit or “pull” systemic T cells in from a “prime”. In our recent Cancer Research paper (Atukorale et al. 2019) and additional preliminary data, we report on the development of a “pull” strategy based on a novel immunostimulatory nanoparticle (immuno-NP) that is significant due to key engineering design features. Immuno-NPs co-encapsulate two synergistic immune agonists on the same particle, cdGMP, an agonist of the STING pathway, and MPLA, an agonist of the TLR4 pathway, to promote a robust production of proinflammatory Type I interferon ß in target APCs. Immuno-NPs can be safely delivered in the systemic blood circulation to achieve widespread and preferential deposition in the tumor perivascular regions that are rich in their target APCs. Immuno-NPs drive a powerful local self-amplifying anti-tumor immune response that harnesses otherwise “exhausted” immunosuppressed local CD8+ T cells as the key effectors of tumor clearance, which suggests highly effective “cold-to-hot” TME reprogramming. Our central hypothesis is that precise coupling of a standard lymph node-directed CD8+ T cell vaccine “prime” with a tumor-directed immuno-NP “pull” for a novel “prime-pull” approach can provide the key missing link for effective cancer vaccination. Specific Aim 1 will identify optimal function of an immuno-NP pull in terms of immuno-NP design and co-treatment with anti-PD1. Specific Aim 2 will develop a precise “prime-pull” coupling schedule. Specific Aim 3 will evaluate safety and toxicity for effective dose/scheduling “prime-pull” regimens. Dr. Atukorale's career goals are to establish a nanomaterials-based cancer immuno-engineering laboratory as an independent investigator. She will develop immuno-nanomaterials tools that drive, quantify, and interrogate immunity, specifically in the context of lethal cancers. Dr. Atukorale's strong career development plan includes significant new research collaborations, a senior advisory committee, research presentations, faculty-level workshops, and plans for subsequent grant proposals. Her future sponsoring institution will be based in both Schools of Medicine and Engineering, in direct line with her highly interdisciplinary research interests.