Remodeling host immunity in oral cancer with personalized RNA nanoparticle vaccines

项目总结/摘要 口腔鳞状细胞癌（Oral cavity squamous cell carcinoma，OCSCC）是一种侵袭性强、死亡率高、生存率低的恶性肿瘤 最大限度的治疗后，如手术和放化疗率。免疫抑制性肿瘤 微环境（TME）是对传统和基于免疫的疗法的反应的主要障碍， ~15%的复发性头颈癌患者对免疫检查点抑制剂有反应。骨髓细胞 富含TME，TME是T细胞功能的关键介质，可以积极影响临床结果， 消极的。我们试图了解骨髓细胞对免疫抑制性TME的贡献， 提出以有利的方式调节这些细胞的策略，以增强OCSCC肿瘤杀伤。 我们的研究小组已经开发出一种新的疫苗治疗平台，可以重新编程肿瘤内和 外周髓样细胞区室转化为抗肿瘤状态。该平台利用临床上 可翻译的脂质纳米颗粒（NPs），与个性化的肿瘤衍生mRNA（TDRNA）组合， 同时作为疫苗和免疫调节剂。我们已经证明 TDRNA-NP疫苗在OCSCC临床前模型中具有显著的抗肿瘤活性，并与 免疫检查点抑制剂。目的一：探讨TDRNA-NP诱导髓系细胞凋亡的机制 通过研究疫苗诱导的骨髓细胞增殖、活化和 OCSCC临床前模型的运输。在目标2中，我们将确定骨髓细胞的机制作用， 在TDRNA-NP疫苗和免疫检查点抑制剂之间的协同作用中， OCSCC。在目标3中，我们将检查TDRNA-NP在客户拥有的 患有自发性口腔鳞状细胞癌的猫。这些研究将使我们深入了解 髓样细胞在OCSCC中的作用，并提出一种有前途的疫苗技术， 首次人体临床试验私家侦探是一位头颈外科肿瘤学家， 目睹了头颈癌对患者的日常影响，并认识到需要 通过转化研究改善患者护理。她是头颈部的活跃成员 肿瘤学项目，得到了她所在部门的大力支持，并拥有一个由世界各地的 著名的肿瘤免疫学专家/翻译研究人员和头颈外科医生。这 指导培训和教育计划已精心设计的研究和职业目标 让私家侦探成为一名头颈癌免疫专家， 翻译研究员总而言之，这项提案有很大的潜力， 并将为P.I.提供大量的培训和指导。成为 独立调查员

PROJECT SUMMARY/ABSTRACT Oral cavity squamous cell carcinoma (OCSCC) is a very aggressive and deadly disease with poor survival rates following maximal treatments such as surgery and chemoradiotherapy. The immunosuppressive tumor microenvironment (TME) is a major barrier of response to traditional and immune based therapies with only ~15% of patients with recurrent head and neck cancer responding to immune checkpoint inhibitors. Myeloid cells are; abundant in the TME, key mediators of T cell function, and can influence clinical outcomes both positively and negatively. We seek to understand the contribution of myeloid cells to the immunosuppressive TME and advance strategies to modulate these cells in a favorable way, to enhance OCSCC tumor killing. Our group has developed a novel vaccine treatment platform that can reprogram the intratumoral and peripheral myeloid cell compartment to an anti-tumor state. This platform leverages the use of clinically translatable lipid nanoparticles (NPs), combined with personalized tumor derived mRNA (TDRNA) that simultaneously functions as both a vaccine and an immunomodulating agent. We have demonstrated that TDRNA-NP vaccines have significant anti-tumor activity in OCSCC preclinical models and synergize with immune checkpoint inhibitors. In Aim 1, we will determine the mechanism of TDRNA-NP induced myeloid cell mediated immune responses by investigating vaccine induced myeloid cell proliferation, activation and trafficking in preclinical models of OCSCC. In Aim 2, we will identify the mechanistic role of myeloid cells in the synergy between TDRNA-NP vaccines and immune checkpoint inhibitors in murine models of OCSCC. In Aim 3, we will examine the safety, efficacy and immunogenicity of TDRNA-NPs in client-owned felines with spontaneously occurring oral squamous cell carcinoma. These studies will give us insight into the role of the myeloid cell compartment in OCSCC and advance a promising vaccine technology towards first-in-human clinical trials. The P.I. of this project is a head and neck surgical oncologist and witnesses the daily impact head and neck cancer has on patients and recognizes the need to improve patient care through translational research. She is an active member of the Head and Neck oncology program, is strongly supported by her department, and has a mentoring team comprised of world renowned expert tumor immunologist/translational researchers, and head and neck surgeon-scientists. This mentored training and educational program has been carefully designed with research and career objectives that will allow the P.I. to progress toward becoming an expert head and neck cancer immunologist and translational researcher. In summary, this proposal has significant potential to dramatically impact the lives of patients with OCSCC and will provide substantial training and mentorship for the P.I. to become an independent investigator.