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

项目总结 尽管传统的癌症疫苗有望带来变革，但自那以来，它们的临床反应一直很差。 疫苗特异性的全身性T细胞通常不能运输到免疫抑制的“冷”肿瘤。传统疫苗 仅产生淋巴结源性增强或系统CD8 T细胞的“初始”，这些细胞被训练成 全面寻找和清除特定靶点肿瘤细胞。然而，传统的战略一直是 目光短浅，因为他们未能开发出方法来将这些T细胞招募到“冷”肿瘤中 通过建立强大的局部免疫抑制屏障推动的微环境(TME) 主要是由功能失调的先天免疫细胞造成的。我们的策略寻求对功能失调的肿瘤居住者重新编程 先天抗原提呈细胞(APC)，如树突状细胞(DC)和巨噬细胞，通过驱动局部抗 促炎症细胞因子梯度重塑非炎症性TME的肿瘤免疫反应 从“冷”到“热”，从炎症到“热”，以招募或“拉入”全身性T细胞。在我们最近的癌症中 研究论文(Atukorale等人2019年)和其他初步数据，我们报告了 基于一种新型免疫刺激纳米颗粒(免疫-NP)的“拉”策略，该策略由于密钥而具有重要意义 工程设计特点。免疫纳米粒共包裹两种协同免疫激动剂 颗粒，刺痛途径激动剂cdGMP和TLR4途径激动剂mpla，以促进 在靶APC中强健地产生促炎I型干扰素？免疫纳米粒可以安全地输送 在体循环中实现肿瘤血管周围的广泛和优先沉积 目标APC丰富的地区。免疫纳米粒驱动强大的局部自我放大抗肿瘤 免疫反应利用其他“耗尽”的免疫抑制局部CD8 T细胞为关键 肿瘤清除的效应者，这表明了高效的从冷到热的TME重新编程。我们的中央 假设是标准的淋巴导向CD8 T细胞疫苗与 肿瘤导向免疫核糖核蛋白“拉”为一种新的“素拉”方法，可提供有效的关键缺失环节 癌症疫苗接种。具体目标1将根据免疫NP确定免疫NP拉动的最佳功能 设计并与抗PD1共治疗。《特定目标2》将制定一份精确的“质数-拉力”耦合时间表。 具体目标3将评估有效剂量/时间安排的“优质”方案的安全性和毒性。Dr。 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，作为 独立调查员。她将开发免疫纳米材料工具来驱动、量化和审问 免疫，特别是在致命性癌症的背景下。Atukorale博士强有力的职业发展计划包括 重要的新研究合作、高级咨询委员会、研究演示、教职员工级别 讲习班，以及后续赠款提案的计划。她未来的赞助机构将设在这两个地方 她毕业于医学院和工程学院，直接符合她高度跨学科的研究兴趣。

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.