Remodeling host immunity in oral cancer with personalized RNA nanoparticle vaccines

利用个性化 RNA 纳米颗粒疫苗重塑口腔癌宿主免疫力

• 批准号: 10549678
• 负责人: Natalie Lea Silver
• 金额: $ 15.53万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549678
• 关键词: Remodeling; host; immunity; oral; cancer

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.

项目摘要/摘要 口腔鳞状细胞癌（OCSCC）是一种非常侵略性和致命的疾病，生存率差 最大程度治疗（例如手术和化学疗法）后的率。免疫抑制性肿瘤 微环境（TME）是对传统和免疫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。髓样细胞 是; TME丰富，TME，T细胞功能的关键介体，并且可以积极影响临床结果 和负面。我们试图了解髓样细胞对免疫抑制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。 我们的小组开发了一个新型的疫苗处理平台，可以重新编程肿瘤内和 外周髓样细胞室至抗肿瘤状态。该平台利用临床上的使用 可翻译的脂质纳米颗粒（NP），结合了个性化的肿瘤衍生的mRNA（TDRNA） 同时充当疫苗和免疫调节剂。我们已经证明了 TDRNA-NP疫苗在OCSCC临床前模型中具有显着的抗肿瘤活性，并与 免疫检查点抑制剂。在AIM 1中，我们将确定TDRNA-NP诱导髓样细胞的机理 通过研究疫苗诱导髓样细胞增殖，激活和 贩运OCSCC的临床前模型。在AIM 2中，我们将确定髓样细胞的机械作用 在TDRNA-NP疫苗和免疫检查点抑制剂之间的协同作用中 OCSCC。在AIM 3中，我们将检查客户拥有的TDRNA-NP的安全性，功效和免疫原性 猫具有自发发生的口服鳞状细胞癌。这些研究将使我们深入了解 髓样细胞室在OCSCC中的作用，并将有希望的疫苗技术推向 首次人类临床试验。 P.I.这个项目是头颈外科肿瘤学家和 目击者每日撞击头和颈部癌对患者产生，并认识到有必要 通过翻译研究改善患者护理。她是头部和脖子的活跃成员 肿瘤学计划得到她的部门的强烈支持，并拥有一个由世界组成的指导团队 著名的专家肿瘤免疫学家/转化研究人员以及头颈外科医生科学家。这 指导的培训和教育计划是通过研究和职业目标进行了精心设计的 这将允许P.I.朝着成为专家头和颈部癌症免疫学家和 翻译研究人员。总而言之，该提议具有巨大的潜力，可以极大地影响生活 OCSCC的患者将为P.I提供大量培训和指导。成为一个 独立研究者。