Modeling Risk for Hypogammaglobulinemia, Infections, and Mortality with Chimeric Antigen Receptor (CAR) T-cell Therapy

项目总结： 这份提案详细说明了一项为期五年的研究培训计划，该计划将使Sara Barmettler医学博士实现她的 成为一名独立的临床研究人员的目标，专注于改善患者的预后 原发和继发性免疫缺陷。巴梅特勒博士是哈佛医学院的医学讲师 (HMS)和麻省总医院(MGH)过敏免疫学医学助理，曾 表现出学术生产力和对临床研究的坚定承诺。她之前受过的训练和 免疫缺陷的研究和其他B细胞靶向治疗的免疫学结果调查 (包括迄今为止接受利妥昔单抗治疗的最大队列患者)，已经建立了技能和经验 对实现她提出的研究目标至关重要。 这项研究建议将促进我们对感染的免疫风险因素的理解， 嵌合抗原受体(CAR)T细胞治疗后的发病率、死亡率和生活质量下降。目标1 利用大量的患者回顾队列来确定对免疫的影响和临床意义 CAR T细胞治疗后的低丙种球蛋白血症。回归模型和贝叶斯网络分析将 用于定义发生感染和不良结局的风险因素，并形成临床风险 预测模型。目的2将评估低丙种球蛋白血症和免疫球蛋白替代治疗的影响 关于发病率、死亡率和生活质量，并评估早期干预的成本-效果。在完成 这些目标，巴梅特勒博士将解决我们在使用后免疫失调知识的关键空白 CAR T细胞疗法的最终目标是改善患者的预后。 巴梅特勒博士将在卡洛斯·卡马戈教授的指导下进行这项工作 国际公认的临床流行病学专家，具有出色的指导记录。Dr。 巴梅特勒组建了一支由流行病学、生物统计学、B- 细胞免疫学、CAR T细胞疗法和传染病，它们的支持将有助于这一项目的成功 项目。在MGH和HMS特殊的培训环境中，Barmettler博士将完成课程和 高级生物统计技术和流行病学方面的培训、领导力和负责任的研究工作。 本职业发展建议书中概述的培训和指导计划，以及 MGH和HMS出色的合作机会和智力环境将使Barmettler博士 为了达到研究和教育的目的，从而确立自己作为一名独立医生的地位- 在高级生物统计学技术和免疫缺陷机制方面具有专业知识的科学家。

PROJECT SUMMARY: This proposal details a five-year research training program that will allow Sara Barmettler, MD to achieve her goal of becoming an independent clinical researcher focused on improving outcomes among patients with primary and secondary immunodeficiency. Dr. Barmettler is an Instructor in Medicine at Harvard Medical School (HMS) and Assistant in Medicine in Allergy-Immunology at Massachusetts General Hospital (MGH) who has demonstrated academic productivity and a strong commitment to clinical research. Her prior training and research in immune deficiency and investigating immunologic outcomes in other B-cell targeted therapies (including the largest cohort to date of rituximab-treated patients), have established the skills and experience critical for achieving her proposed research aims. The research proposal will advance our understanding of immunologic risk factors for infections, morbidity, mortality, and decreased quality of life after chimeric antigen receptor (CAR) T-cell therapy. Aim 1 utilizes a large retrospective cohort of patients to determine the immunologic impact and clinical significance of hypogammaglobulinemia following CAR T-cell therapy. Regression models and Bayesian network analysis will be used to define risk factors for development of infections and poor outcomes and to develop a clinical risk prediction model. Aim 2 will evaluate the impact of hypogammaglobulinemia and immunoglobulin replacement on morbidity, mortality, and quality of life and evaluate cost-effectiveness of early intervention. In accomplishing these aims, Dr. Barmettler will address critical gaps in our knowledge of immune dysregulation following the use of CAR T-cell therapy with the ultimate goal of improving patient outcomes. Dr. Barmettler will perform this work under the mentorship of Professor Carlos Camargo, an internationally recognized expert in clinical epidemiology with an outstanding track record of mentorship. Dr. Barmettler has assembled a team of mentors and collaborators with expertise in epidemiology, biostatistics, B- cell immunology, CAR T-cell therapy, and infectious disease, whose support will contribute to the success of this project. In the exceptional training environment at MGH and HMS, Dr. Barmettler will complete coursework and training in advanced biostatistical techniques and epidemiology, leadership, and responsible conduct of research. The training and mentoring plans outlined in this Career Development proposal, along with the outstanding collaborative opportunities and intellectual environment at MGH and HMS, will allow Dr. Barmettler to achieve the research and educational aims and to, thereby, establish herself as an independent physician- scientist with expertise in advanced biostatistical techniques and mechanisms of immune deficiency.