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Exploring the combinatorial efficacy between chemotherapy and T cell checkpoint inhibition and the role of cellular senescence

探索化疗和 T 细胞检查点抑制之间的组合功效以及细胞衰老的作用

基本信息

批准号：
10443549
负责人：
MATTHEW J BOTT
金额：
$ 26.01万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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/10443549
关键词：
Affect Autologous Basic Science Biological Assay CDK4 gene Cancer Biology Cancer Etiology Cell Aging Cell Cycle Arrest Cell Death Cells Chest Cisplatin Clinical Coculture Techniques Combination Drug Therapy Data Development Drug Combinations Educational Curriculum Environment Faculty Future Gene Expression Profile Genes Goals Growth Human Immune Immune checkpoint inhibitor Immuno-Chemotherapy Immunocompetent Immunologic Surveillance Immunooncology Immunotherapy In Vitro Induced Mutation Inflammation Mediators International Knowledge Laboratories Lung Neoplasms MEKs Malignant neoplasm of lung Mediating Mediator of activation protein Memorial Sloan-Kettering Cancer Center Mentorship Methods Modeling Mutagens Mutation Spectra Non-Small-Cell Lung Carcinoma Nonmetastatic Organoids Pathway interactions Patient Care Patient-Focused Outcomes Patients Phenotype Phosphotransferases Platinum Population Prediction of Response to Therapy Production Randomized Clinical Trials Regimen Research Research Personnel Resected Role Sampling Scientific Inquiry Signal Pathway Specimen Stimulator of Interferon Genes Structure System T-Lymphocyte TP53 gene Technical Expertise Testing Translational Research Tumor Immunity Tumor-Derived Tumor-Infiltrating Lymphocytes Work anti-PD-L1 base cancer therapy career checkpoint inhibition chemotherapy combinatorial conventional therapy cytokine cytotoxicity drug discovery efficacy evaluation immune checkpoint blockade immunogenicity immunoregulation improved outcome in vitro Assay in vivo inhibitor interest knowledge base lung cancer cell member mortality mouse model neoplastic cell novel novel drug combination patient population randomized trial rational design response senescence standard of care surgical service targeted treatment transcriptome transplant model treatment response tumor

项目摘要

PROJECT SUMMARY / ABSTRACT Lung cancer is the leading cause of cancer-related mortality nationwide. In patients with metastatic non-small cell lung cancer, recent randomized trials have demonstrated superior efficacy of combined chemotherapy and T cell checkpoint blockade over conventional treatment. These studies have made combination chemotherapy and T cell checkpoint blockade the new standard of care for patients with lung cancer. However, the mechanisms contributing to the combinatorial efficacy of chemo-immunotherapy remain unknown. Therefore, drug combinations are determined based on historical regimens for lung cancer rather than scientific rationale. Our laboratory has a strong interest in understanding the mechanisms underlying treatment responses as a means of discovering new cancer treatments. The proposal described here builds on our previous work, which identified a combination of targeted therapies that potently induces cellular senescence. In addition to demonstrating durable growth arrest, these senescent cells secrete an array of cytokines that facilitate immune surveillance and tumor cell clearance. Interestingly, our preliminary data suggest that a similar senescent state can be induced by the standard chemotherapy for lung cancer. We hypothesize that this senescence may contribute to the clinically observed combinatorial efficacy between chemotherapy and T cell checkpoint blockade. We propose to characterize chemotherapy-induced senescence, with a particular emphasis on secreted immunomodulatory cytokines. We will leverage orthogonal in vitro and in vivo systems to explore the relevance of senescence to adaptive immunosurveillance, with the goal of determining whether senescence indeed contributes to cytotoxicity in the context of T cell checkpoint inhibition. In addition, we will interrogate tumor specimens from patients treated with chemotherapy, immune checkpoint blockade, or the combination to document the relevance of chemotherapy-induced senescence in patients with NSCLC. The data generated by this proposal will have direct relevance to the current state of NSCLC treatment, and they will facilitate the development of additional, potentially novel, drug combinations. These studies will be led by Dr. Matthew Bott, a junior faculty member on the thoracic surgical service at Memorial Sloan Kettering Cancer Center (MSK) with an interest in lung cancer and immunotherapy. The research will be carried out under the combined mentorship of Dr. Scott Lowe, an international leader in cancer biology, and Dr. Jedd Wolchok, a highly accomplished expert in translational immuno-oncology. MSK offers an outstanding environment for a career in basic and translational research. To achieve his goal of becoming an independent researcher, Dr. Bott has developed a structured curriculum of activities aimed at broadening his knowledge base, expanding his technical skills, and sharpening his methods for scientific inquiry.

项目总结/摘要肺癌是全国癌症相关死亡率的主要原因。转移性非小细胞肺癌患者细胞肺癌，最近的随机试验已经证明联合化疗的上级疗效，与常规治疗相比，T细胞检查点阻断。这些研究使得联合化疗和T细胞检查点封锁的新标准治疗肺癌患者。但有助于化学免疫疗法的组合功效的机制仍然未知。因此，我们认为，药物组合是基于肺癌的历史治疗方案而不是科学原理来确定的。我们的实验室对理解治疗反应的机制有浓厚的兴趣，发现新的癌症治疗方法。这里描述的建议建立在我们以前的工作基础上，确定了一种有效诱导细胞衰老的靶向治疗组合。除了这些衰老细胞表现出持久的生长停滞，它们分泌一系列细胞因子，监测和肿瘤细胞清除。有趣的是，我们的初步数据表明，可以通过肺癌的标准化疗诱导。我们假设这种衰老可能有助于临床观察到的化疗和T细胞检查点之间的组合疗效封锁我们建议对化疗诱导的衰老进行表征，特别强调分泌性衰老。免疫调节细胞因子。我们将利用正交的体外和体内系统来探索适应性免疫监视，目的是确定衰老是否真的在T细胞检查点抑制的情况下有助于细胞毒性。另外，我们会审问肿瘤来自接受化疗、免疫检查点阻断或联合治疗的患者的标本，记录NSCLC患者化疗诱导衰老的相关性。产生的数据该提案将与NSCLC治疗的现状直接相关，开发额外的、潜在的新型药物组合。这些研究将由马修·博特博士领导，他是哈佛大学胸外科服务的一名初级教员。 Memorial Sloan Kettering Cancer Center（MSK），对肺癌和免疫疗法感兴趣。的研究将在国际癌症领域的领导者斯科特·洛博士的联合指导下进行。 Jedd Wolchok博士，一位在转化免疫肿瘤学方面非常有成就的专家。MSK提供了一个优秀的环境，在基础和转化研究的职业生涯。为了实现他成为一名作为一名独立研究员，博特博士开发了一套结构化的活动课程，旨在拓宽他的知识基础，扩大他的技术技能，并锐化他的科学探究方法。