Impact of lymph node sparing on the anti-tumor response for head and neck cancer treated with radiation and immunotherapy

淋巴结保留对放射和免疫治疗头颈癌抗肿瘤反应的影响

• 批准号: 10449726
• 负责人: Mary-Keara Boss
• 金额: $ 12.42万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-03
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449726
• 关键词: Affect; Agonist; Animal Model; Antigens; Antitumor Response; Archives; Automobile Driving; B-Lymphocytes; Biological Assay; Blood; CD8B1 gene; Cancer Model; Cancer Patient; Canis familiaris; Carcinoma; Cell Density; Cells; Clinical; Clinical Data; Combination immunotherapy; Data; Dose; Europe; Flow Cytometry; Goals; Head and Neck Cancer; Human; Immune; Immune response; Immunity; Immunohistochemistry; Immunologics; Immunology; Immunotherapy; Inflammatory; Ligands; Lymph Node Tissue; Mentorship; Metastatic Neoplasm to Lymph Nodes; Monoclonal Antibodies; Mouth Carcinoma; Mus; Natural Killer Cells; Neoplasm Metastasis; OX40; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Population; Pre-Clinical Model; Primary Neoplasm; Prognosis; Program Development; Radiation; Radiation Oncologist; Radiation therapy; Regulatory T-Lymphocyte; Reporting; Research; Rodent; Role; Sampling; Scientist; Site; T cell response; T-Cell Depletion; Testing; Treatment outcome; Tumor Immunity; United States; advanced disease; anti-tumor immune response; antigen-specific T cells; base; canine model; career; career development; clinically relevant; comparative; design; draining lymph node; effector T cell; experimental study; head and neck cancer patient; high risk; immunosuppressed; improved; improved outcome; innovation; interest; irradiation; lymph nodes; mouse model; neoplasm immunotherapy; neoplastic cell; novel strategies; novel therapeutics; patient response; pre-clinical; radiation effect; standard of care; transcriptome sequencing; translational cancer research; translational scientist; tumor; tumor growth; tumor microenvironment

Abstract As a board-certified veterinary radiation oncologist and radiobiologist, I am committed to, and excited for, a career in translational cancer research as a physician scientist. My long-term career goal is to develop into an independent veterinary clinician scientist, proficient in designing and performing innovative radiation research, with a focused interest in tumor microenvironmental effects of radiation therapy and immunotherapy to improve treatment outcomes for patients with head and neck cancer. Head and neck cancer (HNC) is common in the United States and Europe and the prognosis is poor for patients with advanced disease. Stereotactic body radiation therapy (SBRT), which allows delivery of high dose, high precision radiation in a few fractions, is a novel therapy that can be used to treat HNC patients. Evidence exists that SBRT is a more potent activator of anti-tumor immune responses compared to conventional radiotherapy. Emerging preclinical and clinical data suggest SBRT combined with immunotherapy has the potential to convert immunologically “cold” (immunosuppressed) tumors into “hot” (inflamed) tumors. SBRT and IO combinations can stimulate effector T cell responses to each patient’s tumor. HNC patients with high risks for lymph node metastasis typically receive RT targeted to their primary tumor and regional lymph nodes (RLN) in order to eradicate latent metastatic tumor cells; however, RLNs are critical sites for generating immune responses, and RLN irradiation is likely to destroy the immune cells responsible for anti-tumor responses. Based on my preliminary data that SBRT caused depletion of T cell density and expansion of immunosuppressive immune cell populations in RLNs compared to RLNs spared from RT, we propose to study how RLN irradiation affects local and systemic anti-tumor immunity when combined with RT and IO. We will test our hypotheses with orthotopic murine head and neck cancer models and in canine cancer patients who have developed oral carcinoma. For the study, we will use the local tumor immunotherapy combination of agonistic OX-40 monoclonal antibody + TLR9 ligand, which has demonstrated positive tumor microenvironmental immune effects in mice and dogs. If we demonstrate RT+IO and RLN sparing improves outcomes in translational preclinical models of advanced HNC, the results of this project would challenge the current standard of care and clinical paradigm surrounding radiation, immunotherapy, and elective RLN irradiation for patients with advanced HNC. Through the K01 career development program, I will have the opportunity to delve deeper into radiation and immunology research and grow as an independent translational scientist through the direct influence, support, and guidance of my strong mentorship team, Dr. Steven Dow, Dr. Xiao-Jing Wang, and Dr. Sana Karam.

抽象的 作为董事会认证的兽医肿瘤学家和放射生物学家，我致力于并为此感到兴奋 作为物理科学家转化癌症研究的职业。我的长期职业目标是发展成一个 独立的兽医临床科学家，精通设计和进行创新的辐射研究， 对放射疗法和免疫疗法的肿瘤微环境效应的重点是改善 头颈癌患者的治疗结果。 头颈癌（HNC）在美国和欧洲很常见，患者的预后很差 患有晚期疾病。立体定向身体放射疗法（SBRT），允许高剂量递送，高剂量 一些分数中的精度辐射是一种可用于治疗HNC患者的新型疗法。存在证据 与常规放射疗法相比，该SBRT是抗肿瘤免疫调查的更潜在的激活剂。 新兴的临床前和临床数据表明SBRT与免疫疗法结合有可能转化 免疫学上“冷”（免疫抑制）肿瘤成“热”（发炎）肿瘤。 SBRT和IO组合可以 刺激对每个患者肿瘤的效应T细胞反应。淋巴结风险高的HNC患者 转移通常接收针对其原发性肿瘤和区域淋巴结（RLN）的RT 消除潜在的转移性肿瘤细胞；但是，RLN是产生免疫调查的关键部位，并且 RLN辐照可能会破坏负责抗肿瘤反应的免疫力。 根据我的初步数据，SBRT导致T细胞密度的部署和扩展 与免于RLN相比，RLN中的免疫抑制性免疫细胞群体，我们建议研究 当与RT和IO结合使用时，RLN辐射如何影响局部和全身性抗肿瘤免疫。我们将测试 我们使用原位鼠头和颈部癌模型以及具有的犬类癌患者的假设 发育的口腔癌。在研究中，我们将使用局部肿瘤免疫疗法的组合 OX-40单克隆抗体 + TLR9配体，该抗体表现为阳性肿瘤微环境免疫 对小鼠和狗的影响。 如果我们演示了RT+IO和RLN，则可以改善高级翻译临床前模型的结果 HNC，该项目的结果将挑战当前的护理标准和临床范式。 晚期HNC患者的放射，免疫疗法和选择性RLN辐照。通过K01职业 开发计划，我将有机会深入研究辐射和免疫学研究和 通过直接影响，支持和指导，成为独立的转化科学家 指导团队，史蒂文·陶（Steven Dow）博士，王王博士和萨娜·卡拉姆（Sana Karam）博士。