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

使用嵌合抗原受体 (CAR) T 细胞疗法模拟低丙种球蛋白血症、感染和死亡的风险

基本信息

批准号：
10621771
负责人：
Sara Barmettler
金额：
$ 19.39万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-24 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621771
关键词：
Address Adult Age Antibodies B cell therapy B-Lymphocytes Bayesian Analysis Biometry CAR T cell therapy CD19 gene Characteristics Clinical Clinical Research Communicable Diseases Coupled Data Development Diagnosis Dose Early Intervention Early identification Education Environment Epidemiology FDA approved Frequencies Future General Hospitals Goals Health Health Care Costs Healthcare Systems Hematologic Neoplasms Hypersensitivity Immune Immune System Diseases Immunoglobulins Immunologic Deficiency Syndromes Immunologic Monitoring Immunologics Immunology Immunomodulators Immunophenotyping Infection International Intervention K-Series Research Career Programs Knowledge Leadership Life Lymphopenia Malignant - descriptor Malignant Neoplasms Massachusetts Medicine Mentors Mentorship Methods Modeling Monitor Morbidity - disease rate Outcome Outcome Measure Patient Outcomes Assessments Patient-Focused Outcomes Patients Pediatric cohort Peripheral Physicians Population Productivity Protocols documentation Quality of life Questionnaires Recommendation Refractory Relapse Replacement Therapy Research Research Personnel Research Proposals Research Training Retrospective cohort Risk Risk Factors Scientist Serum Severities Surface Antigens Techniques Training Training Programs Tx receptor Work cancer diagnosis career career development chimeric antigen receptor chimeric antigen receptor T cells clinical epidemiology clinical risk clinically significant cohort comorbidity cost cost effective cost effectiveness cost-effectiveness evaluation cytokine release syndrome experience high risk hypogammaglobulinemia improved improved outcome infection risk instructor longitudinal analysis medical schools models and simulation mortality patient subsets professor prospective receptor responsible research conduct risk mitigation risk prediction risk prediction model risk stratification rituximab screening sex skills success therapeutic target tumor

项目摘要

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.

项目摘要：该建议详细介绍了一项为期五年的研究培训计划，该计划将使医学博士Sara Barmettler实现她成为一名独立临床研究人员的目标，致力于改善患者的结局原发性和继发性免疫缺陷。 Barmettler博士是哈佛医学院医学教练（HMS）和马萨诸塞州综合医院（MGH）的过敏性免疫学助理证明了学术生产力和对临床研究的坚定承诺。她先前的培训和免疫缺乏和研究其他B细胞靶向疗法中的免疫结局的研究（包括利妥昔单抗治疗的患者的最大队列）已经建立了技能和经验实现她提出的研究目的至关重要。研究建议将提高我们对感染免疫学风险因素的理解，嵌合抗原受体（CAR）T细胞治疗后的发病率，死亡率和降低的生活质量。目标1 利用大量的回顾性患者来确定免疫学影响和临床意义 CAR T细胞治疗后的低磁性血症。回归模型和贝叶斯网络分析将用于定义感染和不良结局发展的危险因素，并发展临床风险预测模型。 AIM 2将评估低磁性血症和免疫球蛋白替代的影响关于发病率，死亡率和生活质量，并评估早期干预的成本效益。完成这些目的，Barmettler博士将在使用后的免疫失调知识中解决关键差距 CAR T细胞疗法的最终目标是改善患者预后。 Barmettler博士将在Carlos Camargo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。博士巴默特勒（Barmettler）召集了一组导师和合作者，拥有流行病学，生物统计学，b-的专业知识细胞免疫学，汽车T细胞疗法和传染病，其支持将有助于这一成功项目。在MGH和HMS的杰出培训环境中，Barmettler博士将完成课程，并高级生物统计技术和流行病学，领导和负责任的研究的培训。这项职业发展计划中概述了培训和指导计划， MGH和HMS的杰出合作机会和智力环境将允许Barmettler博士为了实现研究和教育目标，从而确立自己是独立的医生 - 具有高级生物统计技术和免疫缺陷机制的专业知识的科学家。