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