New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer

项目摘要 头颈部鳞状细胞癌(HNSCC)是一种侵袭性极强的疾病，总体生存率较低。 尽管免疫检查点阻断(ICB)取得了成功，但目前形式的免疫治疗受益于 15%的HNSCC患者。因此，迫切需要新的战略来实现强有力的和 持久的免疫反应，毒性最小。我们在此应用程序中的目标是设计和开发新的 诱导和增强T细胞对HPV+HNSCC反应的技术工具。为此，我们有 设计了一种纳米疫苗递送载体，可以有效地递送抗原和佐剂分子 对抗原提呈细胞产生强烈的T细胞反应，并具有强大的细胞毒活性。此外，我们 已经确定了一种通过改变肠道微生物群来驾驭免疫系统的新策略，以进一步 放大纳米疫苗引发的T细胞反应。在这里，我们试图进行结构-功能研究，以了解 这些生物材料如何与我们的免疫系统交互，并应用从这些基础知识中获得的知识 增强T细胞对HPV+HNSCC反应的研究。特别是，我们将解决以下问题 通过应用药物传递、生物工程和疫苗学的原理来回答问题。我们可以利用我们的策略吗？ 促进抗原和佐剂向抗原提呈细胞的递送，改善全身和局部T细胞 活体内的反应？我们能否利用我们的疫苗递送技术来释放T细胞的全部细胞毒潜力 细胞与HNSCC内的反向免疫抑制？我们能否通过改变肠道微生物群来提高疗效 联合免疫疗法？我们能否在HPV+HNSCC的原位模型中展示它们的有效性， 包括HNSCC的基因工程小鼠模型？这些研究可能会导致一种新的战略 利用我们的免疫系统作为HPV+HNSCC的潜在治疗方法。该提案充分回应了 PAR-19-172将：(1)推动精确免疫调节创新技术的成熟，(2) 创造多种佐剂输送技术，以及(3)加强NIDCR的免疫疗法 优先疾病。

Project Summary Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive disease with poor overall survival. Despite the success of immune checkpoint blockade (ICB), current forms of immunotherapy benefit less than 15% of HNSCC patients. Therefore, there exists a critical need for new strategies for achieving powerful and durable immune responses with minimal toxicity. Our objective in this application is to design and develop new technological tools for inducing and potentiating T-cell responses against HPV+ HNSCC. To this end, we have engineered a nanoparticle vaccine delivery vehicle that can efficiently deliver antigens and adjuvant molecules to antigen-presenting cells and achieve strong T-cell responses with robust cytotoxic potential. In addition, we have identified a novel strategy for harnessing the immune system by altering the gut microbiome to further amplify nanovaccine-primed T-cell responses. Here, we seek to conduct structure-function studies to understand how these biomaterials interface with our immune system and apply the knowledge gained from these basic studies to potentiate T-cell responses against HPV+ HNSCC. In particular, we will address the following questions by applying the principles of drug delivery, bioengineering, and vaccinology. Can we utilize our strategy to promote antigen and adjuvant delivery to antigen-presenting cells, and improve systemic and local T-cell responses in vivo? Can we employ our vaccine delivery technology to unleash the full cytotoxic potential of T- cells and reverse immunosuppression within HNSCC? Can we alter the gut microbiome to boost efficacy of combination immunotherapy? Can we demonstrate their efficacy in orthotopic models of HPV+ HNSCC, including genetically engineered mouse model of HNSCC? These studies may lead to a novel strategy for harnessing our immune system as the potential treatment of HPV+ HNSCC. The proposal is fully responsive to PAR-19-172 as it will: (1) drive the maturation of an innovative technology for precise immune modulation, (2) create technologies for versatile adjuvant delivery, and (3) enhance the immunotherapeutics for an NIDCR priority disease.