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.

项目概要 头颈鳞状细胞癌 (HNSCC) 也是由烟草、乙醇和其他致癌物质引起的 作为致癌人乳头瘤病毒（HPV）。尤其是HPV阴性的HNSCC死亡率很高， 局部和区域疾病的主要治疗选择，包括手术、放射和 化疗，导致显着的发病率。 PD-1 抑制剂已被批准用于治疗复发性/转移性 HNSCC，但尚未取得进展 回复率低至 14-20%。此外，最近的一项 III 期试验表明，当 PD-1 抑制剂与放化疗结合使用针对肿瘤和淋巴结的大辐射场。尽管 肿瘤免疫微环境是免疫治疗活性的关键，引流淋巴结的作用 对免疫疗法的功效知之甚少，传统疗法对抗肿瘤免疫的影响 值得进一步调查。我们的初步数据表明淋巴结照射或手术切除引流 淋巴结完全阻断PD-1抑制剂的抗肿瘤活性，手术破坏淋巴管 单独使用通道同时保持引流淋巴结完整也会阻碍免疫治疗反应。 从机制上讲，我们已经确定引流节点中的 cDC1 和 B 细胞抗原呈递细胞是关键的免疫细胞 协调抗肿瘤免疫反应的效应器。此外，使用 PD-1 进行免疫放射治疗的 I 期试验 抑制剂与淋巴保留立体定向放射 (SBRT) 相结合显示出显着的 67% HNSCC 患者的完全病理缓解率。我们的中心假设是完整的、功能性的 引流淋巴管和淋巴结对于抗肿瘤免疫至关重要，并且保留淋巴管 HNSCC 的 IRT 将最大限度地提高抗肿瘤反应。为了探索这个假设，我们将使用动物模型 HPV 阴性 HNSCC 1) 确定引流前哨淋巴结在生成和形成过程中的作用 在 HPV 阴性的免疫治疗和基于 SBRT 的免疫放射治疗期间协调免疫反应 HNSCC，2) 通过优化治疗顺序、放射治疗，最大限度地提高 HNSCC 的免疫治疗反应 靶向并增强引流淋巴结中的抗原呈递。为了在患者身上验证这一假设， 我们将通过临床试验定义与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 引流前哨淋巴结在协调抗肿瘤免疫反应中的作用，确定优化的 HNSCC 的测序和新型组合免疫疗法，并定义患者的免疫特征 HSNCC 对免疫放射治疗有完全反应。这些见解将指导和改进设计 利用引流淋巴结协调抗肿瘤免疫反应的治疗策略 改善 HNSCC 和其他实体瘤患者的预后。