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

用于新型“启动”癌症疫苗接种的肿瘤定向免疫刺激纳米粒子

基本信息

批准号：
10470310
负责人：
Prabhani Atukorale
金额：
$ 19.43万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470310
关键词：
Advisory Committees Agonist Antigen Targeting Antigen-Presenting Cells Applications Grants Automobile Driving Beds Blood Circulation CD8-Positive T-Lymphocytes Cancer Vaccines Cells Chemotherapy and/or radiation Clinical Collaborations Combined Modality Therapy Coupled Coupling Data Data Reporting Dendritic Cells Deposition Development Development Plans Dose Educational workshop Encapsulated Engineering Ensure Faculty Future Goals Guanosine Monophosphate Hepatotoxicity Histopathology Hydrophobicity Immune Immune checkpoint inhibitor Immunity Immunosuppression In Vitro Inflammatory Institution Interdisciplinary Study Interferon Type I Interferon-beta Investigation Kinetics Laboratories Link Lipid A Lipids Longitudinal Studies Macrophage Activation Malignant Neoplasms Memory Methods PD-1 inhibitors Paper Pathway interactions Periodicity Perivascular Neoplasm Production Public Health Publishing Recurrence Regimen Research Research Personnel Safety Schedule Stimulator of Interferon Genes T-Lymphocyte TLR4 gene Testing Toxic effect Training Treatment Protocols Tumor Antigens Vaccination Vaccines Vision anti-PD-1 anti-tumor immune response anticancer research base cancer vaccination career career development cell motility cytokine design engineering design exhaust hydrophilicity immune activation immunoengineering immunosuppressed in vivo innovation interest lymph nodes macrophage malignant breast neoplasm medical schools melanoma mouse model nanomaterials nanoparticle neoplastic cell novel particle pre-clinical recruit response success surface coating tool tumor tumor microenvironment vaccination strategy

项目摘要

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.

项目摘要尽管有变革性的承诺，但传统的癌症疫苗以来的临床反应较差疫苗特异性的全身T细胞通常无法传播免疫抑制的“冷”肿瘤。传统疫苗仅生成淋巴结衍生的增强或被训练的全身CD8+ T细胞的“原始” 全面寻找和消除特定的靶肿瘤细胞。但是，传统策略已经短视的是，他们未能开发出将这些T细胞募集到“冷”肿瘤的方法微环境（TME）通过建造强大的当地免疫抑制驱动器来发展主要由功能失调的先天免疫细胞。我们的策略旨在重新编程功能失调的肿瘤居民通过驱动局部抗抗原的抗原细胞（APC），例如树突状细胞（DC）和巨噬细胞肿瘤免疫反应，具有促炎性细胞因子梯度，可重塑非炎症的TME 从“ Prime”中招募或“招募”系统性T细胞的“冷”发炎和“热”。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，我们报告了基于新型免疫刺激性纳米颗粒（免疫NP）的“拉力”策略，由于关键而具有重要意义工程设计功能。免疫NP共同服用两种协同免疫激动剂粒子，CDGMP，刺激途径的激动剂，而MPLA（TLR4途径的激动剂）以促进A 在目标APC中，促炎性I型干扰素ß的强大产生。可以安全地交付免疫NP 在系统性血液循环中，以实现肿瘤周围的宽度和首选沉积富含目标APC的地区。免疫NP驱动强大的本地自我扩增抗肿瘤免疫反应，以其他方式利用其他“精疲力尽”的免疫抑制局部CD8+ T细胞作为钥匙肿瘤清除的效应子，这表明高效的“冷 - 热” TME重编程。我们的中心假设是标准淋巴结定向的CD8+ T细胞疫苗“ Prime”的精确耦合与A 用于新颖的“ Prime-Pull”方法的肿瘤指导的免疫NP“拉”可以提供有效的关键丢失链接癌症疫苗接种。特定的目标1将根据免疫NP确定免疫NP拉力的最佳功能设计和与抗PD1共同处理。特定的AIM 2将制定精确的“ Prime-Pull”耦合时间表。特定的目标3将评估安全性和毒性，以进行有效的剂量/调度“素水平”方案。博士 Atukorale的职业目标是建立基于纳米材料的癌症免疫工程实验室独立研究者。她将开发免疫纳米材料工具来驱动，量化和询问免疫，特别是在致命癌的背景下。 Atukorale博士的强大职业发展计划包括重要的新研究合作，高级咨询委员会，研究演示文稿，教职员工级讲习班，以及随后的赠款提案的计划。她未来的赞助机构将基于医学和工程学学校与她高度跨学科的研究兴趣直接相符。