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，总体生存率很低。 尽管免疫检查点阻断（ICB）取得了成功，但目前形式的免疫疗法的益处小于 15%的HNSCC患者。因此，迫切需要制定新的战略， 持久的免疫反应和最小的毒性。我们的目标是设计和开发新的 用于诱导和增强针对HPV+ HNSCC的T细胞应答的技术工具。为此我们 设计了一种纳米颗粒疫苗递送载体，可以有效地递送抗原和佐剂分子， 抗原呈递细胞，并实现具有强大细胞毒性潜力的强T细胞应答。另外我们 已经确定了一种通过改变肠道微生物组来利用免疫系统的新策略， 增强纳米疫苗引发的T细胞应答。在这里，我们寻求进行结构-功能研究，以了解 这些生物材料如何与我们的免疫系统相互作用，并应用从这些基本的 研究以增强针对HPV+ HNSCC的T细胞应答。我们将特别处理以下问题 通过应用药物输送，生物工程和疫苗学的原则来解决问题。我们能不能利用我们的策略 以促进抗原和佐剂递送至抗原呈递细胞，并改善全身和局部T细胞免疫应答， 体内反应？我们能否利用我们的疫苗输送技术来释放T细胞的全部细胞毒性潜力？ 细胞和逆转HNSCC内的免疫抑制？我们能改变肠道微生物组来提高 联合免疫疗法我们能否证明它们在HPV+ HNSCC原位模型中的疗效， 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策略， 利用我们的免疫系统作为HPV+ HNSCC的潜在治疗方法。该建议充分回应了 PAR-19-172将：（1）推动精确免疫调节创新技术的成熟，（2） 创造多功能佐剂递送技术，和（3）增强NIDCR的免疫治疗 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.