Optimizing immunoradiotherapy for HNSCC

项目摘要 头颈部鳞状细胞癌(HNSCC)也是由烟草、乙醇和其他致癌物引起的 作为致癌的人乳头瘤病毒(HPV)。特别是，HPV阴性的HNSCC死亡率高， 局部和地区性疾病的主要治疗选择，包括手术、放射治疗和 化疗，会引起很大的发病率。PD-1抑制剂被批准用于复发/转移性HNSCC 应答率低，为14-20%。此外，最近的一项第三阶段试验显示，当PD-1 抑制剂与放化疗相结合，使用针对肿瘤和淋巴结的大辐射场。而当 肿瘤免疫微环境是免疫治疗活性的关键，引流淋巴结在肿瘤免疫治疗中的作用 免疫疗法的疗效和常规疗法对抗肿瘤免疫的影响知之甚少。 值得进一步调查。我们的初步数据显示结节照射或手术移除引流管。 淋巴结完全阻断PD-1抑制剂的抗肿瘤活性，并手术切断淋巴管 在保持完整的引流淋巴结的同时，单独的通道也会阻止免疫治疗反应。 从机制上讲，我们已经确定引流结节中的cDC1和B细胞抗原提呈细胞是关键免疫细胞。 协调抗肿瘤免疫反应的效应器。此外，使用PD-1的免疫放射治疗的I期试验 抑制剂联合淋巴保留立体定向放射治疗(SBRT)显示显着的67% HNSCC患者的完全病理应答率。我们的中心假设是完整的，有功能的 引流淋巴管和淋巴结对于抗肿瘤免疫和淋巴保护至关重要 HNSCC中的IRT将最大限度地发挥抗肿瘤作用。为了探索这一假设，我们将使用 HPV阴性的HNSCC到1)确定引流前哨淋巴结在产生和 HPV阴性患者免疫治疗与SBRT免疫放射治疗中免疫反应的协调 HNSCC，以及2)通过优化治疗序列、放射治疗，最大化HNSCC的免疫治疗反应 靶向，并增强引流淋巴结中的抗原提呈。为了在患者身上验证这一假设， 我们将定义与临床试验的主要病理反应相关的免疫表型。 HPV阴性HNSCC患者的新辅助免疫放射治疗该项目的完成将阐明 前哨淋巴结引流在协同抗肿瘤免疫反应中的作用 HNSCC的测序和新的组合免疫疗法，并确定患者的免疫特征 对HSNCC的免疫放射治疗完全有效。这些见解将指导和改进设计 利用引流淋巴来协调抗肿瘤免疫反应的治疗策略 改善HNSCC和其他实体肿瘤患者的预后。

Project Summary Head and neck squamous cell carcinoma (HNSCC) is driven by tobacco, ethanol and other carcinogens as well as oncogenic human papilloma virus (HPV). In particular, HPV negative HNSCC has a high rate of mortality and the main curative treatment options for local and regional disease, including surgery, radiation, and chemotherapy, incur significant morbidity. PD-1 inhibitors are approved for recurrent/metastatic HNSCC yet have low response rates of 14-20%. Furthermore, a recent Phase III trial demonstrated no benefit when a PD-1 inhibitor was combined with chemoradiation using large radiation fields targeting tumor and lymph nodes. While the tumor immune microenvironment is key to the activity of immunotherapy, the role of draining lymph nodes in the efficacy of immunotherapy is poorly understood and the impact of conventional therapies anti-tumor immunity deserves further investigation. Our preliminary data demonstrate nodal irradiation or surgical removal of draining lymph nodes completely blocks the anti-tumor activity of PD-1 inhibitors, and surgical disruption of lymphatic channels alone while maintaining intact draining lymph nodes also blocks immunotherapy responses. Mechanistically, we have identified cDC1 and B-cell antigen presenting cells in draining nodes as key immune effectors coordinating anti-tumor immune responses. Further, a Phase I trial of immunoradiotherapy using PD-1 inhibitors combined with lymphatic sparing stereotactic radiation (SBRT) demonstrates a remarkable 67% complete pathologic response rate in HNSCC patients. Our central hypothesis is that intact, functional draining lymphatics and lymph nodes are critical for anti-tumor immunity and that lymphatic preserving IRT in HNSCC will maximize anti-tumor responses. To explore this hypothesis, we will use animal models of HPV negative HNSCC to 1) determine the role of the draining sentinel lymph nodes in generating and coordinating immune responses during immunotherapy and SBRT based immunoradiotherapy in HPV negative HNSCC, and 2) maximize immunotherapy responses in HNSCC by optimizing treatment sequencing, radiation targeting, and enhancing antigen presentation in draining lymph nodes. To validate this hypothesis in patients, we will define immune phenotypes that correlate with major pathologic responses from a clinical trial of neoadjuvant immunoradiotherapy in HPV negative HNSCC patients. Completion of this project will elucidate the role of draining sentinel lymph nodes in coordinating anti-tumor immune responses, identify optimized sequencing and novel combinatorial immune therapies in HNSCC, and define immune signatures in patients with complete responses to immunoradiotherapy in HSNCC. These insights will guide and improve the design of therapeutic strategies that leverage draining lymph nodes in coordinating anti-tumor immune response and improve outcomes in HNSCC and other solid tumor patients.