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.

项目概要/摘要 口腔鳞状细胞癌 (OCSCC) 是一种极具侵袭性和致命性的疾病，生存率很低 最大治疗（例如手术和放化疗）后的比率。免疫抑制性肿瘤 微环境（TME）是对传统疗法和免疫疗法产生反应的主要障碍 约 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 是; TME 中含量丰富，是 T 细胞功能的关键介质，可以积极影响临床结果 和消极的。我们试图了解骨髓细胞对免疫抑制性 TME 的贡献，并 推进以有利的方式调节这些细胞的策略，以增强 OCSCC 肿瘤的杀伤能力。 我们小组开发了一种新型疫苗治疗平台，可以重新编程瘤内和 外周骨髓细胞室进入抗肿瘤状态。该平台利用临床 可翻译的脂质纳米颗粒 (NP) 与个性化肿瘤衍生 mRNA (TDRNA) 相结合， 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。在目标1中，我们将确定TDRNA-NP诱导骨髓细胞的机制 通过研究疫苗诱导的骨髓细胞增殖、激活和介导的免疫反应 OCSCC 临床前模型的贩运。在目标 2 中，我们将确定骨髓细胞的机制作用 TDRNA-NP 疫苗与免疫检查点抑制剂在小鼠模型中的协同作用 OCSCC。在目标 3 中，我们将检查 TDRNA-NP 在客户拥有的药物中的安全性、有效性和免疫原性 患有自发性口腔鳞状细胞癌的猫科动物。这些研究将使我们深入了解 骨髓细胞区室在 OCSCC 中的作用，并推进有前途的疫苗技术 首次人体临床试验。 P.I.该项目的负责人是一名头颈外科肿瘤学家 目睹头颈癌对患者的日常影响，并认识到有必要 通过转化研究改善患者护理。她是头颈协会的活跃成员 肿瘤学项目得到了她所在部门的大力支持，并拥有一支由世界各地的人组成的指导团队 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 指导培训和教育计划是根据研究和职业目标精心设计的 这将使 P.I.朝着成为一名头颈癌免疫学家的目标迈进， 翻译研究员。总之，该提案具有极大的潜力，可以极大地影响人们的生活 OCSCC 患者，并将为 P.I. 提供大量培训和指导。成为一个 独立调查员。