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.

项目摘要 该提案概述了马克·李博士的五年培训计划，哲学博士、目的是让他做好准备 作为一名医生兼科学家的独立学术研究生涯。李博士于一九九九年完成博士研究， 免疫学在哈佛医学院的一部分，结合医学博士/博士计划，目前是一个 布里格姆妇女医院的讲师和委员会认证的输血医学医生。李博士的 职业发展计划将建立在他在人类免疫学的背景，增加教学培训和初级 在计算肿瘤学和癌症研究方面的研究经验。在这项工作中，李博士将得到以下方面的指导： 博士Matthew Meyerson是肺癌基因组学的国际领导者， 已经过渡到独立学术研究职位的医生-科学家，以及科学家 咨询委员会由德高望重的医生科学家组成（埃利泽货车艾伦博士，马塞拉毛斯博士， 和大卫芭比博士），他们在计算肿瘤学、癌症免疫学和癌症生物学方面具有专业知识。 杰出的研究环境和设施提供给李博士，包括实验室空间在达纳- 法伯癌症研究所和布罗德研究所。此外，利用内部广泛的职业发展资源， 在哈佛附属医院系统，李博士将进一步发展科学领导的关键职业技能， 实验室管理、研究交流和资助写作。拟议的长期目标 研究是应用新技术来鉴定癌症基因组中肿瘤反应性T细胞的靶点， 为了从根本上了解癌症患者的免疫反应， 应答尽管免疫疗法--特别是免疫检查点阻断--已经彻底改变了 对于非小细胞肺癌（NSCLC）患者的治疗，大多数患者没有反应。 因此，提高免疫疗法对无应答者的疗效仍然是癌症研究的关键优先事项。 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，具有 导致癌症患者的主要病理反应，包括对检查点阻断无反应者。 然而，目前有限的一组定义明确的肿瘤反应性TCR-以及识别TCR的技术困难， 肿瘤抗原/TCR对-目前限制了可以用这些新的肿瘤抗原/TCR对治疗的NSCLC患者的数量。 治疗李博士最近开发了一种高通量的方法，可以对数千个 假定的T细胞靶点，并将应用该方法鉴定NSCLC患者中T细胞受体的靶点 肿瘤和血液标本。本项目的成功完成将使我们能够更全面地了解 富集肿瘤反应性T细胞的细胞标志物（Aim 1），以及更完整地了解 外周血中的肿瘤反应性T细胞响应PD-1阻断（Aim 2）。除了正规培训外， 拟议中的研究将使李博士作为一名学术性的物理学家和科学家开始一项独立的职业生涯。