Optimizing immunoradiotherapy for HNSCC

优化 HNSCC 的免疫放射治疗

• 批准号: 10804468
• 负责人: Joseph A Califano
• 金额: $ 69.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10804468
• 关键词: Ablation; Agonist; Animal Model; Anti-CD47; Antigen Presentation; Antigen-Presenting Cells; Antitumor Response; Architecture; B-Lymphocytes; CD4 Positive T Lymphocytes; CD47 gene; CD8B1 gene; Carcinogens; Cells; Clinical; Clinical Data; Clinical Trials; Data; Dendritic Cells; Eating; Ethanol; Excision; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immune checkpoint inhibitor; Immune response; Immunologic Surveillance; Immunologics; Immunotherapy; In complete remission; Investigation; Localized Disease; Lymphatic; Malignant Neoplasms; Metastatic/Recurrent; Modeling; Morbidity - disease rate; Neoadjuvant Therapy; Nivolumab; Nodal; Oncogenic; Operative Surgical Procedures; Outcome; Pathologic; Patients; Phagocytosis; Phase; Phenotype; Primary Neoplasm; Radiation; Radiation therapy; Radioimmunotherapy; Regional Disease; Research; Role; Sentinel Lymph Node; Signal Transduction; Solid Neoplasm; T cell clonality; T-Cell Activation; T-Lymphocyte; Therapeutic; Tobacco; Toll-like receptors; Treatment-related toxicity; Tumor Antigens; Tumor Immunity; anti-cancer; anti-tumor immune response; cancer immunotherapy; cell type; chemoradiation; chemotherapy; combinatorial; conventional therapy; curative treatments; cytokine; cytotoxic; design; draining lymph node; effector T cell; head and neck cancer patient; improved; improved outcome; inhibitor; insight; irradiation; lymph nodes; lymphatic vessel; mortality; mouse model; neoplastic cell; novel; phase I trial; phase III trial; preservation; programmed cell death protein 1; response; trafficking; treatment optimization; tumor; tumor-immune system interactions

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.

项目摘要 头部和颈部鳞状细胞癌（HNSCC）也由烟草，乙醇和其他致癌物驱动 作为致癌人乳头状瘤病毒（HPV）。特别是，HPV负HNSCC具有很高的死亡率和 局部和区域疾病的主要治疗方法，包括手术，辐射和 化学疗法，产生明显的发病率。 PD-1抑制剂被批准用于复发/转移性HNSCC 低回应率为14-20％。此外，最近的III期试验在PD-1时表明没有任何好处 使用靶向肿瘤和淋巴结的大辐射场与化学放疗结合。尽管 肿瘤免疫微环境是免疫疗法活性的关键，这是排干淋巴结在 免疫疗法的功效知之甚少，常规疗法的抗肿瘤免疫力的影响 值得进一步调查。我们的初步数据表明淋巴结辐射或外科手术消耗 淋巴结完全阻断了PD-1抑制剂的抗肿瘤活性，并淋巴的手术破坏 单独的通道同时保持完整的排水淋巴结也可以阻止免疫疗法反应。 从机械上讲，我们已经确定了排水节点中的CDC1和B细胞抗原呈现细胞为关键免疫 效应子协调抗肿瘤免疫反应。此外，使用PD-1进行免疫放射治疗的I期试验 抑制剂结合淋巴较高的立体定向辐射（SBRT）表现出显着的67％ HNSCC患者的完全病理反应率。我们的中心假设是完整的功能性 排水淋巴和淋巴结对于抗肿瘤免疫至关重 HNSCC中的IRT将最大化抗肿瘤反应。为了探讨这一假设，我们将使用 HPV负HNSCC至1）确定排水前哨淋巴结在生成和 在HPV阴性的免疫疗法和基于SBRT的免疫放射治疗过程中，协调免疫反应 HNSCC和2）通过优化治疗测序，辐射，在HNSCC中最大化免疫疗法反应 靶向并增强排水淋巴结中的抗原表现。为了验证患者的这一假设， 我们将定义与与临床试验的主要病理反应相关的免疫表型 HPV阴性HNSCC患者中的新辅助免疫亚治疗。该项目的完成将阐明 排水前哨淋巴结在协调抗肿瘤免疫反应中的作用，确定优化 HNSCC中的测序和新型组合免疫疗法，并定义患者的免疫特征 对HSNCC中免疫放射治疗的完全反应。这些见解将指导和改进设计 在协调抗肿瘤免疫反应和 改善HNSCC和其他实体瘤患者的预后。