Improving Treatment Algorithms for Veterans with Oropharyngeal Cancer

改善口咽癌退伍军人的治疗算法

• 批准号: 10152351
• 负责人: VLAD C SANDULACHE
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152351
• 关键词: Acute; Affect; Algorithms; American Joint Committee on Cancer; Area; Biological; Biometry; CD8B1 gene; Cells; Cellular Structures; Chronic; Clinical; Clinical Trials; Complex; Data; Diagnosis; Disease; Dose; Enrollment; Environment; Epidemiology; Etiology; Evaluation; Exposure to; Gene Expression Profiling; General Population; Human Characteristics; Human Papillomavirus; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunohistochemistry; Immunomodulators; Incidence; Inflammatory Response; Light; Link; Lymphocyte; Lymphocytic Infiltrate; Malignant Neoplasms; Manuals; Medical center; Mentorship; Molecular; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Normal tissue morphology; Oncogenic Viruses; Oropharyngeal Squamous Cell Carcinoma; Outcome; Patients; Play; Population; Principal Investigator; Recording of previous events; Recurrence; Refractory; Regimen; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Secondary to; Selection for Treatments; Site; Smoker; Smoking; Smoking History; Soft Palate; Staging; Survival Rate; T-Lymphocyte; Tobacco; Tonsil; Toxic effect; Training Activity; Treatment Failure; Treatment Protocols; Unresectable; Up-Regulation; Veterans; Veterans Health Administration; Work; anticancer research; base; cancer therapy; chemoradiation; clinically relevant; cohort; conventional therapy; design; effective therapy; experience; experimental study; follow-up; human model; immunomodulatory strategy; immunomodulatory therapies; improved; malignant oropharynx neoplasm; meetings; military veteran; mouse model; novel; online course; optimal treatments; patient population; standard care; therapy resistant; tobacco exposure; tongue root; treatment effect; treatment response; tumor; tumor immunology; tumor-immune system interactions

Oropharyngeal cancer is rapidly increasing in incidence in the veteran population, fueled largely by exposure to the human papilloma virus (HPV). Although survival for oropharyngeal squamous cell carcinoma associated with the human papilloma virus (HPV+OPSCC) is excellent in the general population, it remains dismal in the veteran population, with nearly 1 in 2 patients dying of their disease within 5 years of diagnosis. This disproportionally poor survival is thought to be driven in part by tumors which are less responsive to chemo-radiation treatment regimens. Preliminary data from our group and others suggests this decreased treatment response may be in part driven by tobacco exposure, which is extremely prevalent among Veterans with HPV+OPSCC. The hypothesized mechanism of action is a tobacco induced, immunosuppressive environment which inhibits the normal anti-tumor activity of lymphocytes and other immune cells during cancer treatment. In the current proposal, we will first characterize and quantify the relative effect of tobacco exposure on survival in Veterans with HPV+OPSCC (Aim 1). This is critical in light of the newly implemented 8th Edition of the AJCC Staging Manual which dramatically down-stages OPSCC based on HPV status (HPV associated vs non-HPV associated), but does not consider the potentially critical impact of tobacco exposure on survival. Given the widespread, and extensive tobacco exposure we and others have demonstrated in Veterans with OPSCC, this represents an important clinical and translational first step in potentially improving survival for Veterans with this disease. We will then characterize the Th1 T-lymphocyte and myeloid derived suppressor cell (MDSC) components of the tumor immune microenvironment (TIME) in HPV+OPSCC tumors as a function of tobacco exposure (Aim 2). This will allow us to provide support for our mechanistic hypothesis and to define the relationship between tobacco exposure and changes in the TIME of HPV+OPSCC. Finally, we will compare the TIME characteristics of HPV+OPSCC tumors which fail to respond to conventional chemo-radiation treatment regimens to the TIME of HPV+OPSCC tumors which do respond to treatment, in order to define an immune signature associated with treatment resistance in this disease site (Aim 3). Together, these experiments will allow us to: 1) define a clinically relevant effect size for tobacco exposure vis a vis HPV+OPSCC survival and 2) begin to define a mechanistic link between tobacco exposure and TIME dependent treatment response. Successful completion of the proposed research will allow us to more appropriately prognosticate survival in Veterans with HPV+OPSCC, identify patients which may be candidates for treatment escalation using immunomodulatory agents (i.e. checkpoint inhibitors) and patients which should not be enrolled in clinical trials aimed at de-escalation of chemo-radiation regimens in order to decrease normal tissue toxicity. In parallel with the proposed research, the Principal Investigator will engage in training activities designed to provide increased facility and expertise in the areas of Epidemiology and Biostatistics as well as Tumor Immunology, through a combination of formal and online course work, participation in institutional, local and national meetings and direct interactions with a Mentorship Committee with appropriate expertise in these 3 areas of cancer research.

口咽癌在退伍军人群体中的发病率迅速增加， 主要是由于接触人乳头状瘤病毒（HPV）。虽然口咽部存活 与人乳头状瘤病毒（HPV+OPSCC）相关的鳞状细胞癌非常好 在一般人群中，退伍军人群体中的情况仍然令人沮丧，近二分之一的患者 诊断后 5 年内死于疾病。人们认为这种不成比例的低生存率 部分是由对化学放射治疗方案反应较差的肿瘤驱动的。 我们小组和其他人的初步数据表明，治疗反应下降可能是 部分原因是烟草暴露，这在退伍军人中极为普遍 HPV+OPSCC。假设的作用机制是烟草诱导的免疫抑制 抑制淋巴细胞和其他免疫细胞正常抗肿瘤活性的环境 在癌症治疗期间。 在当前的提案中，我们将首先描述和量化烟草的相对影响 暴露对患有 HPV+OPSCC 的退伍军人的生存影响（目标 1）。鉴于新的情况，这一点至关重要 实施了第 8 版 AJCC 分期手册，大大降低了 OPSCC 的分期 基于 HPV 状态（HPV 相关性与非 HPV 相关性），但不考虑 烟草暴露对生存的潜在严重影响。鉴于广泛、广泛 我们和其他人在患有 OPSCC 的退伍军人中证明了烟草暴露，这代表了 这是重要的临床和转化的第一步，有可能提高退伍军人的生存率 疾病。 然后我们将表征 Th1 T 淋巴细胞和骨髓源性抑制细胞 HPV+OPSCC 肿瘤中肿瘤免疫微环境 (TIME) 的 (MDSC) 组成部分为 烟草暴露的函数（目标 2）。这将使我们能够为我们的机制提供支持 假设并定义烟草暴露与时间变化之间的关系 HPV+OPSCC。最后，我们将比较 HPV+OPSCC 肿瘤的 TIME 特征， HPV+OPSCC 的时间对常规放化疗治疗方案没有反应 对治疗有反应的肿瘤，以确定与相关的免疫特征 该疾病部位的治疗耐药性（目标 3）。总之，这些实验将使我们能够：1) 定义烟草暴露相对于 HPV+OPSCC 存活率的临床相关效应大小，以及 2) 开始定义烟草暴露与时间依赖性治疗之间的机制联系 回复。成功完成拟议的研究将使我们能够更适当地 预测患有 HPV+OPSCC 的退伍军人的生存率，确定可能的候选患者 使用免疫调节剂（即检查点抑制剂）和患者进行治疗升级 不应参加旨在降低放化疗方案的临床试验 以减少正常组织的毒性。 在拟议研究的同时，首席研究员将参加培训 旨在提供流行病学领域更多设施和专业知识的活动 通过正式课程和在线课程相结合的生物统计学和肿瘤免疫学 工作、参加机构、地方和国家会议以及与 指导委员会在这三个癌症研究领域拥有适当的专业知识。