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.

摘要 作为一名委员会认证的兽医放射肿瘤学家和放射生物学家，我致力于并为之兴奋， 作为一名医生科学家从事转化癌症研究。我的长期职业目标是发展成为一名 独立兽医临床科学家，精通设计和执行创新的放射研究， 专注于放射治疗和免疫治疗的肿瘤微环境效应，以改善 头颈癌患者的治疗结果。 头颈部癌（HNC）在美国和欧洲很常见，患者预后很差 患有晚期疾病立体定向体部放射治疗（SBRT），其允许递送高剂量、高剂量的放射性物质。 在几个部分中的精确辐射是可用于治疗HNC患者的新颖疗法。证据存在 SBRT是一种比常规放疗更有效的抗肿瘤免疫反应激活剂。 新出现的临床前和临床数据表明，SBRT联合免疫治疗有可能转化为 免疫“冷”（免疫抑制）肿瘤转化为“热”（发炎）肿瘤。SBRT和IO组合可以 刺激效应T细胞对每个患者肿瘤的反应。淋巴结高风险HNC患者 转移瘤通常接受靶向其原发肿瘤和区域淋巴结（RLN）的RT， 根除潜伏的转移性肿瘤细胞;然而，RLN是产生免疫应答的关键部位， RLN辐射可能会破坏负责抗肿瘤反应的免疫细胞。 根据我的初步数据，SBRT引起T细胞密度的耗竭和 免疫抑制免疫细胞群体的RLN相比，从RT幸免于RLN，我们建议研究 RLN照射与RT和IO联合时如何影响局部和全身抗肿瘤免疫。我们将测试 我们的假设与原位小鼠头颈癌模型和犬癌症患者谁有 发展成口腔癌对于本研究，我们将采用局部肿瘤免疫治疗联合激动剂 OX-40单克隆抗体+TLR 9配体，已证实肿瘤微环境免疫阳性 对小鼠和狗的影响。 如果我们证明RT+IO和RLN保留可以改善晚期乳腺癌转化临床前模型的结局， HNC，该项目的结果将挑战当前的护理标准和临床范式， 放射治疗、免疫治疗和选择性喉返神经放射治疗晚期HNC患者。K 01职业生涯 发展计划，我将有机会深入研究辐射和免疫学研究， 成长为一个独立的翻译科学家通过直接影响，支持，和我的强大的指导 导师团队，Steven Dow博士，Xiao-Jing Wang博士和Sana Karam博士。