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

摘要 作为一名获得董事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 以内科科学家的身份从事转译癌症研究。我的长期职业目标是发展成为一名 独立的兽医临床科学家，擅长设计和执行创新的辐射研究， 重点关注肿瘤微环境放射治疗和免疫治疗效果的改善 头颈癌患者的治疗结果。 头颈癌(HNC)在美国和欧洲很常见，患者预后很差 患有晚期疾病。立体定向全身放射治疗(SBRT)，允许提供高剂量、高剂量 精确分次照射是一种可用于治疗HNC患者的新型治疗方法。证据是存在的 与常规放射治疗相比，SBRT是一种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与免疫治疗相结合有可能将 免疫“冷”(免疫抑制)肿瘤转变为“热”(炎症)肿瘤。SBRT和IO组合可以 刺激效应器T细胞对每个患者的肿瘤的反应。高危HNC患者的淋巴转移 转移者通常接受针对其原发肿瘤和区域淋巴结(RLN)的RT，以便 根除潜在的转移肿瘤细胞；然而，RLN是产生免疫反应的关键部位，并且 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导致T细胞密度耗尽和T细胞增殖 与未进行RT的RLN相比，RLN中的免疫抑制免疫细胞群，我们建议研究 当放疗和IO联合应用时，RLN照射如何影响局部和全身抗肿瘤免疫。我们将测试 我们在原位小鼠头颈部癌症模型和犬癌患者中的假设 发展为口腔癌。对于这项研究，我们将使用局部肿瘤免疫治疗联合激动剂 肿瘤微环境免疫阳性的OX-40单抗+TLR9配体 对小鼠和狗的影响。 如果我们证明RT+IO和RLN保留改善了晚期患者翻译前临床模型的结果 HNC，该项目的结果将挑战当前的护理标准和临床范例 晚期HNC患者的放射治疗、免疫治疗和选择性RLN照射。在K01职业生涯中 发展计划，我将有机会更深入地研究辐射和免疫学研究和 在我强大的团队的直接影响、支持和指导下成长为一名独立的翻译科学家 导师团队，Steven Dow博士、王晓静博士和Sana Karam博士。

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.