Remodeling host immunity in oral cancer with personalized RNA nanoparticle vaccines

项目摘要/摘要 口腔鳞状细胞癌(OCSCC)是一种高度侵袭性和致命性的疾病，存活率低。 在手术和放化疗等最大限度治疗后的发病率。免疫抑制肿瘤 微环境(TME)是传统和基于免疫的治疗的主要障碍，仅 约15%的复发性头颈癌患者对免疫检查点抑制剂有反应。髓系细胞 在T细胞功能的关键介质TME中含量丰富，并且可以对临床结果产生积极影响 也是消极的。我们试图了解髓系细胞在免疫抑制TME和 提出以有利的方式调节这些细胞的策略，以增强OCSCC对肿瘤的杀伤。 我们团队已经开发了一种新型疫苗治疗平台，它可以重新编程肿瘤内和 外周髓系细胞室进入抗肿瘤状态。该平台充分利用了临床上 可翻译的脂质纳米粒(NPs)，与个性化的肿瘤来源的mRNA(TDRNA)相结合， 同时起到疫苗和免疫调节剂的作用。我们已经证明了 TDRNA-NP疫苗在口腔鳞癌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。在目标1中，我们将确定TDRNA-NP诱导髓系细胞的机制 研究疫苗诱导的髓系细胞增殖、活化和免疫应答 口腔鳞状细胞癌临床前模型的贩运。在目标2中，我们将确定髓系细胞的机制作用。 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-NPs在客户拥有的患者中的安全性、有效性和免疫原性 患有自发性口腔鳞状细胞癌的猫。这些研究将使我们深入了解 髓系细胞室在口腔鳞状细胞癌中的作用和一种有前景的疫苗技术 这是首例人类临床试验。这个项目的私家侦探是一名头颈外科肿瘤学家 见证了头颈部癌症对患者的日常影响，并认识到有必要 通过转化性研究改善患者护理。她是头部和颈部的活跃成员 肿瘤学项目，得到了她所在部门的大力支持，并拥有一支由World组成的指导团队 著名的肿瘤免疫学家/翻译研究专家，以及头颈外科科学家。这 辅导式培训和教育计划经过精心设计，具有研究和职业目标 这将使私家侦探向成为头颈部癌症免疫学家的专家迈进， 翻译研究员。总而言之，这项提议有很大的潜力极大地影响人们的生活 将为口腔鳞癌患者提供实质性的培训和指导，使其成为 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.