The antigen specificity of tumor-targeting T cells in non-small cell lung cancer

非小细胞肺癌中肿瘤靶向T细胞的抗原特异性

• 批准号: 10590220
• 负责人: Mark N. Lee
• 金额: $ 27.79万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590220
• 关键词: Acceleration; Achyrocline; Adoptive Cell Transfers; Advisory Committees; American; Antigen-Presenting Cells; Antigens; Antitumor Response; Atlases; Blood; Blood specimen; Board Certification; Cancer Biology; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Circulation; Clinical; Clone Cells; Communication; Complex; DNA; Dana-Farber Cancer Institute; Development; Development Plans; Disease remission; Doctor of Medicine; Doctor of Philosophy; Environment; Foundations; Frequencies; Goals; Grant; Hospitals; Human; Immune response; Immunology; Immunooncology; Immunotherapy; Individual; International; Laboratories; Leadership; Lung; Malignant neoplasm of lung; Mediating; Medical; Mentors; Methodology; Methods; Non-Small-Cell Lung Carcinoma; Oligonucleotide Microarrays; Oncology; Pathologic; Patient Selection; Patients; Peptide Receptor; Peptides; Physicians; Positioning Attribute; Professional Competence; Proteins; Recording of previous events; Research; Resource Development; Scientist; Solid Neoplasm; Specimen; System; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Training; Training Programs; Tumor Antigens; United States; Woman; Writing; anticancer research; blood-based biomarker; cancer genome; cancer genomics; career; career development; cost; cytokine; exhaustion; experience; immune checkpoint blockade; instructor; interest; medical schools; migration; neoplastic cell; new technology; novel; novel therapeutics; patient subsets; peripheral blood; programmed cell death protein 1; programs; response; single cell sequencing; stem; transfusion medicine; treatment response; tumor; tumor immunology; tumor specificity

PROJECT SUMMARY This proposal outlines a five-year training program for Dr. Mark Lee, M.D., Ph.D., with the goal of preparing him for an independent academic research career as a physician-scientist. Dr. Lee completed doctoral studies in immunology at Harvard Medical School as part of the combined M.D./Ph.D. program, and is currently an Instructor at the Brigham and Women’s Hospital and a board-certified Transfusion Medicine physician. Dr. Lee’s career development plan will build on his background in human immunology, adding didactic training and primary research experiences in computational oncology and cancer research. In this effort, Dr. Lee will be mentored by Dr. Matthew Meyerson, who is an international leader in lung cancer genomics and has a history of mentoring physician-scientists who have transitioned to independent academic research positions, as well as a Scientific Advisory Committee composed of highly regarded physician-scientists (Dr. Eliezer Van Allen, Dr. Marcela Maus, and Dr. David Barbie) who have expertise in computational oncology, cancer immunology, and cancer biology. The outstanding research environment and facilities available to Dr. Lee include laboratory space at both Dana- Farber Cancer Institute and the Broad Institute. In addition, using extensive career development resources within the Harvard-affiliated hospital system, Dr. Lee will further develop critical career skills in scientific leadership, laboratory management, research communication, and grant writing. The long-term goal of the proposed research is to apply novel technologies to identify the targets of tumor-reactive T cells within cancer genomes, in order to fundamentally understand immune responses in cancer patients and to therapeutically augment these responses. Although immunotherapy – and in particular, immune checkpoint blockade – has revolutionized treatment for select patients with non-small cell lung cancer (NSCLC), the majority of patients fail to respond. Thus, increasing the efficacy of immunotherapy for non-responders remains a critical priority of cancer research. T cell-based therapies, including adoptive cellular therapies and T cell receptor (TCR) bispecific proteins, have led to major pathologic responses in cancer patients, including in non-responders to checkpoint blockade. However, the currently limited set of well-defined tumor-reactive TCRs – and the technical difficulty of identifying tumor antigen/TCR pairs – currently restricts the number of NSCLC patients that can be treated with these novel therapies. Dr. Lee recently developed a high-throughput method that allows functional testing of thousands of putative T cell targets, and will apply this method to identify the targets of T cell receptors in NSCLC patient tumor and blood specimens. Successful completion of this project will enable a more complete understanding of the cellular markers that enrich for tumor-reactive T cells (Aim 1) and a more complete understanding of how tumor-reactive T cells in the peripheral blood respond to PD-1 blockade (Aim 2). Together with formal training, the proposed research will allow Dr. Lee to launch an independent career as an academic physician-scientist.

项目概要 该提案概述了马克·李博士（医学博士、哲学博士）的五年培训计划，目的是让他做好准备 李博士以医师科学家的身份完成了独立的学术研究生涯。 哈佛医学院免疫学作为联合医学博士/博士课程的一部分，目前是一名免疫学博士生。 布莱根妇女医院的讲师和李博士的委员会认证的输血医学医师。 职业发展计划将以他在人类免疫学方面的背景为基础，增加教学培训和初级培训 在这项工作中，李博士将得到计算肿瘤学和癌症研究方面的研究经验。 Matthew Meyerson 博士是肺癌基因组学领域的国际领导者，拥有指导历史 已转为独立学术研究职位的医师科学家，以及科学工作者 咨询委员会由备受尊敬的医师科学家组成（Eliezer Van Allen 博士、Marcela Maus 博士、 和 David Barbie 博士），他们在计算肿瘤学、癌症免疫学和癌症生物学方面拥有专业知识。 李博士拥有出色的研究环境和设施，包括丹纳大学和丹纳大学的实验室空间。 此外，法伯癌症研究所和布罗德研究所还利用了广泛的职业发展资源。 在哈佛大学附属医院系统中，李博士将进一步发展科学领导力方面的关键职业技能， 实验室管理、研究交流和资助申请的长期目标。 研究的目的是应用新技术来识别癌症基因组中肿瘤反应性 T 细胞的靶标， 为了从根本上了解癌症患者的免疫反应并在治疗上增强这些免疫反应 尽管免疫疗法——特别是免疫检查点封锁——已经发生了革命性的变化。 对于某些非小细胞肺癌（NSCLC）患者的治疗，大多数患者未能做出反应。 因此，提高免疫治疗对无反应者的疗效仍然是癌症研究的首要任务。 基于 T 细胞的疗法，包括过继性细胞疗法和 T 细胞受体 (TCR) 双特异性蛋白，已 导致癌症患者发生重大病理反应，包括对检查点封锁无反应的患者。 然而，目前明确的肿瘤反应性 TCR 集有限，而且识别的技术难度也很大 肿瘤抗原/TCR 对——目前限制了可以用这些新型药物治疗的 NSCLC 患者的数量 李博士最近开发了一种高通量方法，可以对数千个患者进行功能测试。 假定的T细胞靶点，并将应用该方法来识别NSCLC患者中T细胞受体的靶点 肿瘤和血液标本的成功完成将使人们能够更全面地了解肿瘤和血液标本。 富集肿瘤反应性 T 细胞的细胞标记物（目标 1）以及更全面地了解如何富集肿瘤反应性 T 细胞 外周血中的肿瘤反应性 T 细胞对 PD-1 阻断做出反应（目标 2）以及正式训练。 拟议的研究将使李博士能够作为一名学术医师科学家开启独立的职业生涯。