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Triggering Innate Immunity in Tumor Cells to Overcome Resistance to Immunotherapy

触发肿瘤细胞的先天免疫以克服对免疫治疗的耐药性

基本信息

批准号：
10117211
负责人：
Jeffrey J. Ishizuka
金额：
$ 27.91万
依托单位：
YALE UNIVERSITY
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：
2020-03-02 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117211
关键词：
ADAR1 Advisory Committees Antibodies Antigen Presentation Antiviral Response Award CCL25 gene CRISPR screen CRISPR/Cas technology CXCL10 gene CXCL11 gene Cell Line Cells Chemicals Chest Clinical Combination immunotherapy Complex Dana-Farber Cancer Institute Disease Double-Stranded RNA Drug Targeting Effectiveness Enzymes Event Fellowship Program Funding Future Genes Genetic Goals Grant Gynecologic Hematology Human I-antigen Immune response Immune system Immunologic Techniques Immunotherapy Infiltration Inflammation Inflammatory Institutes Interferons Interleukin-6 K-Series Research Career Programs Knock-out Lead Major Histocompatibility Complex Malignant Neoplasms Manuscripts Mediating Mediator of activation protein Medical Oncology Mentors Mentorship Minority Modeling Mus Mutation Natural Immunity Natural Killer Cells Nature Neoplasm Transplantation Nucleic Acids Oncology PD-1/PD-L1 PDL1 pathway Patients Phenocopy Phenotype Positioning Attribute Proteins Publishing RANTES RNA Editing Research Research Personnel Resistance Resources Scientist System TREX1 protein Testing Therapeutic Time Training Transplantation Treatment Protocols Tumor-infiltrating immune cells Work antiviral immunity autoinflammatory cancer immunotherapy cancer type checkpoint inhibition chemokine clinical practice cytokine genetic approach genome editing immune checkpoint immune checkpoint blockade improved in vivo in vivo Model innate immune checkpoint instructor medical schools neoplastic cell new therapeutic target novel novel drug class novel strategies novel therapeutic intervention nucleic acid inhibitor overexpression programmed cell death protein 1 programs pseudotoxoplasmosis syndrome recruit resistance mechanism response response biomarker standard of care success targeted treatment tenure track therapeutic development tool tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY: Immune checkpoint inhibition of the PD-1/PD-L1 pathway has demonstrated dramatic and durable clinical benefit for patients in many cancer types and is increasingly being incorporated into standard of care treatment regimens. However, in most tumor types, this strategy is effective only for a minority of patients. As such, there is an urgent need for novel therapeutic approaches to potentiate immune checkpoint blockade and increase the proportion of patients who benefit from it. We recently used in vivo CRISPR screening in transplantable mouse tumor models treated with antibodies targeting PD-1 to identify the RNA editing enzyme, ADAR1, as a novel target for combination immunotherapy. In a manuscript published in Nature, we showed that loss of ADAR1 can overcome two of the most common and challenging mechanisms of resistance to immunotherapy: a lack of infiltration of anti-tumor immune cells in the tumor microenvironment and the loss of antigen presentation by the class I major histocompatibility complex on tumor cells. However, the mechanisms by which loss of ADAR1 achieves these therapeutic goals are unclear. In Aim 1 and Aim 2 of this grant, I propose to define these mechanisms and to elaborate general principles by which resistance to immunotherapy can be overcome. More broadly, the identification of ADAR1 as a target for improving responses to immunotherapy suggests that targeting other enzymes that are associated with a similar auto- inflammatory phenotype in humans could similarly benefit patients treated with immune checkpoint blockade. I propose to test this hypothesis in Aim 3 of this grant. If successful, these results will provide a mechanistic paradigm for overcoming resistance to immunotherapy and identify novel drug targets that trigger a similar mechanism. I am currently a Clinical Fellow in Medical Oncology in the Dana-Farber/Partners CancerCare Hematology and Oncology Fellowship Program. Over 85% of my time is devoted to my ongoing research under the mentorship of Dr. Matthew Meyerson (DFCI, Broad Institute) and Dr. Arlene Sharpe (Harvard Medical School). The remainder of my time is devoted to clinical practice and training at the Dana-Farber Cancer Institute, primarily in thoracic and gynecologic medical oncology. My goal is to successfully transition from senior fellow to research instructor and ultimately to an independent investigator in a tenure-track position. I am applying for the K08 Mentored Clinical Scientist Research Career Development Award to provide the necessary training and funding to achieve this goal. Under the mentorship of Drs. Meyerson and Sharpe, and the guidance of my advisory committee (Drs. Golub, Freeman, Hur and Barbie), I will access the necessary resources and training to develop a successful, independent research program over the funding period of the award.

项目概要： PD-1/PD-L1通路的免疫检查点抑制已经证明是显著和持久的。为许多癌症类型的患者带来临床益处，并越来越多地纳入标准治疗中治疗方案。然而，在大多数肿瘤类型中，这种策略仅对少数患者有效。作为因此，迫切需要新的治疗方法来加强免疫检查点阻断，增加从中受益的患者比例。我们最近使用体内CRISPR筛选，用靶向PD-1的抗体处理的可移植小鼠肿瘤模型以鉴定RNA编辑酶， ADAR 1作为联合免疫治疗的新靶点。在《自然》杂志上发表的一篇手稿中， ADAR 1的缺失可以克服两种最常见和最具挑战性的耐药机制，免疫疗法：肿瘤微环境中抗肿瘤免疫细胞浸润的缺乏和肿瘤微环境中抗肿瘤免疫细胞的丧失。通过肿瘤细胞上的I类主要组织相容性复合体的抗原呈递。然而，机制 ADAR 1的缺失通过何种途径实现这些治疗目标尚不清楚。在本拨款的目的1及目的2中，建议界定这些机制，并制定一般原则，免疫治疗是可以克服的。更广泛地说，将ADAR 1鉴定为改善对免疫疗法的反应表明，靶向与类似的自体免疫相关的其他酶，人类的炎症表型可以类似地使用免疫检查点阻断治疗的患者受益。我我建议在本拨款的目的3中测试这个假设。如果成功，这些结果将提供一个机制，克服免疫治疗耐药性的范例，并确定新的药物靶点，机制我目前是Dana-Farber/Partners CancerCare的肿瘤内科临床研究员血液学和肿瘤学奖学金计划。我85%的时间都花在了研究上在Matthew Meyerson博士（DFCI，Broad Institute）和Arlene Sharpe博士（哈佛）的指导下医学院）。我的其余时间是致力于临床实践和培训在达纳法伯癌症研究所，主要在胸部和妇科肿瘤医学。我的目标是成功过渡到从高级研究员到研究讲师，最终成为终身制的独立调查员位置我正在申请K 08指导临床科学家研究职业发展奖，以提供为实现这一目标提供必要的培训和资金。在迈耶森博士和夏普博士的指导下在我的顾问委员会（Golub博士，Freeman博士，Hur博士和Barbie博士）的指导下，我将访问必要的资源和培训，以制定一个成功的，独立的研究计划，超过资金奖的期限。