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: 10594506
• 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/10594506
• 关键词: Affect; Agonist; Animal Model; Antigens; Antitumor Response; Archives; Automobile Driving; B-Lymphocytes; Biological Assay; Blood; Board Certification; CD8B1 gene; Cancer Model; Cancer Patient; Canis familiaris; Carcinoma; Cell Density; Cells; Clinical; Clinical Data; Combination immunotherapy; Combined Modality Therapy; 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; 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 作为一名经过委员会认证的兽医放射肿瘤学家和放射生物学家，我致力于并对此感到兴奋 作为一名医师科学家，我从事转化癌症研究的职业生涯。 独立兽医临床科学家，精通设计和执行创新辐射研究， 主要关注放射治疗和免疫治疗对肿瘤微环境的影响，以改善 头颈癌患者的治疗结果。 头颈癌（HNC）在美国和欧洲很常见，患者预后较差 立体定向全身放射治疗 (SBRT)，可提供高剂量、高剂量的治疗。 少量的精确放射治疗是一种可用于治疗 HNC 患者的新疗法。 与传统放疗相比，SBRT 是更有效的抗肿瘤免疫反应激活剂。 新兴的临床前和临床数据表明 SBRT 与免疫疗法相结合具有转化的潜力 SBRT 和 IO 组合可以将免疫学上的“冷”（免疫抑制）肿瘤转变为“热”（发炎）肿瘤。 刺激效应 T 细胞对每位淋巴结高风险 HNC 患者的反应。 转移瘤通常接受针对原发肿瘤和区域淋巴结 (RLN) 的放疗，以便 根除潜伏的转移性肿瘤细胞；然而，RLN 是产生免疫反应的关键位点，并且 RLN 照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 导致 T 细胞密度减少和 T 细胞扩增 与未接受 RT 的 RLN 相比，RLN 中的免疫抑制性免疫细胞群，我们建议进行研究 我们将测试 RLN 照射与 RT 和 IO 结合时如何影响局部和全身抗肿瘤免疫。 我们对原位小鼠头颈癌模型以及患有以下疾病的犬癌症患者的假设 在这项研究中，我们将使用激动剂的局部肿瘤免疫治疗组合。 OX-40单克隆抗体+TLR9配体，已显示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 保留可以改善高级临床前转化模型的结果 HNC，该项目的结果将挑战当前的护理标准和临床范式 通过 K01 职业生涯，为晚期 HNC 患者提供放射、免疫治疗和选择性 RLN 照射。 发展计划，我将有机会更深入地研究辐射和免疫学研究 通过我强有力的直接影响、支持和指导，成长为一名独立的转化科学家。 导师团队包括 Steven Dow 博士、王晓静博士和 Sana Karam 博士。