Dissecting mechanisms of resistance underlying CD47-SIRPα inhibition in T-cell lymphomas

剖析 T 细胞淋巴瘤中 CD47-SIRPα 抑制的耐药机制

基本信息

批准号：
10417149
负责人：
Salvia Jain
金额：
$ 26.21万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417149
关键词：
Address Adult Advisory Committees Affect Anti-CD47 Antibodies Antigen Presentation Antitumor Response Area Award B-Cell Lymphomas Binding Biology Blocking Antibodies Blood C57BL/6 Mouse CD47 gene CD47-SIRPα Cancer Center Cell Line Cells Cellular biology Child Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complement Computational Biology Cutaneous Dana-Farber Cancer Institute Data Set Dendritic cell activation Dendritic cell tumor Dependence Development Eating Ensure Environment Focus Groups Foundations Future Genomics Goals Guanosine Triphosphate Phosphohydrolases Hematologist Hematology Heterogeneity Human IgG Receptors IgG1 Immune Immunity Immunocompetent Immunologic Surveillance Immunology Immunophenotyping Immunotherapeutic agent Immunotherapy Inflammasome Integrins International Investigational Therapies Israel Jurkat Cells Ki-1 Large-Cell Lymphoma Knock-out Laboratories Lead Lymphoma Lymphoma cell Macrophage-1 Antigen Malignant Neoplasms Mediating Medical center Mentors Modeling Modernization Molecular Monoclonal Antibodies Multi-Institutional Clinical Trial Mus Orphan Outcome PTPNS1 gene Patients Peripheral Phagocytes Phagocytosis Predisposition Proteins Proteome Proteomics Refractory Refractory Disease Regimen Relapse Reporting Research Research Personnel Research Proposals Research Training Resistance Resources Rest SYK gene Sampling Signal Pathway Signal Transduction Solid Structure Surface Systems Biology T-Cell Lymphoma T-Lymphocyte Therapeutic Therapeutic Human Experimentation Time Training Transgenic Organisms Translational Research Tumor Burden Tumor-associated macrophages Work adaptive immune response adaptive immunity antagonist anti-CD20 base cancer cell cancer immunotherapy career career development clinical care defined contribution design differential expression experience in vivo macrophage mouse model neoplastic cell next generation novel pre-clinical prevent programs receptor recruit resistance mechanism response rituximab single cell sequencing therapeutic target transcriptome transcriptome sequencing treatment response

项目摘要

Project Summary/Abstract: ! Over the recent years immunotherapeutic regimens have revolutionized the fate of solid malignancies and aggressive B-cell lymphomas but T-cell lymphoma (TCL) remains the orphan child. Identification and blockade of the CD47-SIRPa axis has created an opportunity for investigators to harness the innate immune cells. However early results from clinical trials have revealed that disruption of this signaling pathway is insufficient to clear tumor cells by macrophages. Thus, there is an unmet need to identify additional regulators of the macrophage checkpoint that confer resistance to CD47-mediated anti-tumor responses. I recently defined mechanisms by which CD47 antagonists induce anti-TCL response (Blood, 2019). However, marked heterogeneity across TCL models with poor correlation between CD47 expression and phagocytosis have led us to investigate molecular mechanisms that work with CD47 or independently from it in governing TCL recognition and eradication by macrophages. By combining modern next-generation immunophenotyping and single-cell sequencing; I will identify, mechanistically characterize, and therapeutically validate the compensatory signaling dependencies in CD47-resistant TCL models and primary samples. This will lay the foundation for future clinical trials of targeted immunotherapies in TCLs. I am an adult hematologist with substantial clinical and prior research experience in TCL who is seeking K08 support for mentored research in Dr. David Weinstock’s laboratory at Dana-Farber Cancer Institute (DFCI) with Dr. David Avigan, Beth Israel Deaconess Medical Center (BIDMC) acting as a co-mentor. My long-term career objective is to lead an independent research group focused on development of immunotherapy for patients with TCLs at an academic cancer center. The K08 award will provide the protected time I need for advanced training in CD47 biology and immunology, in particular, analysis of large-scale transcriptome and proteome datasets, experimental therapeutics and translational research. I will devote a minimum of 80% of my time to a focused research program on immune therapies for TCLs and will complement this with 20% of my effort dedicated to clinical care for adults with lymphomas. Dana-Faber Harvard Cancer Center (DF/HCC), comprised of DFCI and BIDMC is an internationally recognized research program with a number of expert researchers in the areas of cancer cell biology, immunology and computational biology. I have assembled an oustanding mentoring and advisory committee, consisting of Dr. Francis Luscinskas, Dr. Bruce Horwitz and Dr. Vassiliki Bousiottis, who will guide my research and training experiences. The expertise of my advisory committee will be complemented by a set of additional collaborators who are experts in their respective fields (Dr. Jim Lederer, Dr. Alex Shalek, and Kristen Stevenson). This research proposal is part of a structured plan with scientific, technical, clinical training and career development components with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on immunotherapy and clinical adult hematology.

项目摘要/摘要：！近年来，免疫治疗方案彻底改变了实体恶性肿瘤的命运，侵袭性 B 细胞淋巴瘤，但 T 细胞淋巴瘤 (TCL) 仍是孤儿识别和封锁。 CD47-SIRPa 轴的变化为研究人员利用先天免疫细胞创造了机会。然而，临床试验的早期结果表明，破坏该信号通路不足以因此，识别额外的调节因子的需求尚未得到满足。我最近定义了对 CD47 介导的抗肿瘤反应具有抵抗力的巨噬细胞检查点。 CD47 拮抗剂诱导抗 TCL 反应的机制（Blood，2019）。 CD47 表达与吞噬作用之间相关性较差的 TCL 模型之间的异质性导致我们研究与 CD47 协同作用或独立于 CD47 控制 TCL 的分子机制通过结合现代下一代免疫表型和巨噬细胞的识别和根除。单细胞测序；我将识别、机械表征并治疗验证补偿 CD47抗性TCL模型和初级样品中的信号依赖性这将为研究奠定基础。未来 TCL 靶向免疫疗法的临床试验。我是一名成人血液科医生，在 TCL 拥有丰富的临床和先前研究经验，正在寻求 K08 支持 Dana-Farber 癌症研究所 (DFCI) David Weinstock 博士实验室的指导研究贝斯以色列女执事医疗中心 (BIDMC) 的 David Avigan 博士担任我的长期职业生涯的共同导师。目标是领导一个独立的研究小组，专注于开发针对患有以下疾病的患者的免疫疗法学术癌症中心的 TCL 将为我提供高级培训所需的受保护时间。 CD47生物学和免疫学，特别是大规模转录组和蛋白质组数据集的分析，我将至少投入 80% 的时间来专注于实验疗法和转化研究。 TCL 免疫疗法的研究计划，并将用我 20% 的努力来补充这一计划丹纳法伯哈佛癌症中心 (DF/HCC) 为成人淋巴瘤患者提供临床护理，由 DFCI 和 BIDMC 是一个国际公认的研究项目，拥有以下领域的众多专家研究人员：我在癌症细胞生物学、免疫学和计算生物学方面积累了出色的指导和经验。顾问委员会，由 Francis Luscinskas 博士、Bruce Horwitz 博士和 Vassiliki Bousiottis 博士组成，他们将指导我的研究和培训经验将得到补充。一组其他合作者，他们都是各自领域的专家（Jim Lederer 博士、Alex Shalek 博士和该研究提案是科学、技术、临床培训结构化计划的一部分。和职业发展组成部分，目标是确保我获得成为所需的专业知识一位成功的独立研究者，专注于免疫治疗和临床成人血液学。