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

• 批准号: 10650752
• 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
• 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/10650752
• 关键词: Affect; Autologous; Basic Science; Biological Assay; CDK4 gene; Cancer Biology; Cancer Etiology; Cell Aging; Cell Cycle Arrest; Cell Death; Cell secretion; Cells; Cisplatin; Clinical; Coculture Techniques; Combination Drug Therapy; Combined Modality 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 Stimulation; Immunologic Surveillance; Immunooncology; Immunotherapy; In Vitro; Induced Mutation; Infiltration; Inflammation Mediators; International; Knowledge; Laboratories; Lung Neoplasms; MEKs; Malignant neoplasm of lung; Mediating; Mediator; Memorial Sloan-Kettering Cancer Center; Mentorship; Methods; Modeling; Mutagens; Mutation Spectra; Non-Small-Cell Lung Carcinoma; Organoids; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Phosphotransferases; Platinum; Population; Prediction of Response to Therapy; Production; 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; Thoracic Surgical Procedures; Translational Research; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Work; anti-PD-L1; 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; patient population; randomized trial; randomized, clinical trials; rational design; response; senescence; standard of care; surgical service; targeted treatment; transcriptomic profiling; transplant model; treatment response; tumor

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.

项目概要/摘要 肺癌是全国癌症相关死亡的主要原因。对于转移性非小 细胞肺癌，最近的随机试验证明了联合化疗和联合化疗的优越疗效 T 细胞检查点阻断优于传统治疗。这些研究使联合化疗 T 细胞检查点阻断为肺癌患者提供了新的护理标准。然而， 导致化学免疫疗法联合疗效的机制仍不清楚。所以， 药物组合是根据肺癌的历史治疗方案而不是科学原理来确定的。 我们的实验室对了解治疗反应的潜在机制非常感兴趣 发现新的癌症治疗方法的手段。这里描述的提案建立在我们之前的工作的基础上， 确定了有效诱导细胞衰老的靶向治疗组合。此外 这些衰老细胞表现出持久的生长停滞，分泌一系列促进免疫的细胞因子 监测和肿瘤细胞清除。有趣的是，我们的初步数据表明，类似的衰老状态 可以通过肺癌的标准化疗来诱导。我们假设这种衰老可能 有助于临床观察到化疗和 T 细胞检查点之间的组合疗效 封锁。 我们建议描述化疗引起的衰老的特征，特别强调分泌的衰老 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相关性 衰老与适应性免疫监视的关系，目的是确定衰老是否确实存在 在 T 细胞检查点抑制的情况下有助于细胞毒性。此外，我们还会询问肿瘤 来自接受化疗、免疫检查点阻断或联合治疗的患者的标本 记录了非小细胞肺癌患者化疗引起的衰老的相关性。生成的数据 该提案将与 NSCLC 治疗的现状直接相关，并将促进 开发额外的、潜在新颖的药物组合。 这些研究将由 Matthew Bott 博士领导，他是该校胸外科服务的初级教员。 纪念斯隆凯特琳癌症中心 (MSK) 对肺癌和免疫疗法感兴趣。这 研究将在国际癌症领域领军人物 Scott Lowe 博士的联合指导下进行 Jedd Wolchok 博士是一位在转化免疫肿瘤学领域卓有成就的专家。 MSK 斯隆提供 基础和转化研究职业的良好环境。为了实现他成为一名 作为一名独立研究员，Bott 博士开发了一套结构化的活动课程，旨在扩大他的研究范围。 知识基础，扩展他的技术技能，并提高他的科学探究方法。

项目成果

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non-Small Cell Lung Cancer.

• DOI: 10.1053/j.semtcvs.2020.12.012
• 发表时间: 2021
• 期刊: Seminars in thoracic and cardiovascular surgery
• 影响因子: 2.5
• 作者: Cao C;Guo A;Chen C;Chakos A;Bott M;Yang CJ;Zielinski R;Melfi F
• 通讯作者: Melfi F

Robotic Bronchoscopy for the Diagnosis of Pulmonary Lesions.

用于诊断肺部病变的机器人支气管镜检查。

• DOI: 10.1016/j.thorsurg.2022.08.008
• 发表时间: 2023
• 期刊: Thoracic surgery clinics
• 影响因子: 2.1
• 作者: McLoughlin,KaitlinC;Bott,MatthewJ
• 通讯作者: Bott,MatthewJ

Two-Year Quality of Life Outcomes After Robotic-Assisted Minimally Invasive and Open Esophagectomy.

• DOI: 10.1016/j.athoracsur.2020.09.027
• 发表时间: 2021-09
• 期刊: ANNALS OF THORACIC SURGERY
• 影响因子: 4.6
• 作者: Vimolratana, Marc;Sarkaria, Inderpal S.;Goldman, Debra A.;Rizk, Nabil P.;Tan, Kay See;Bains, Manjit S.;Adusumilli, Prasad S.;Sihag, Smita;Isbell, James M.;Huang, James;Park, Bernard J.;Molena, Daniela;Rusch, Valerie W.;Jones, David R.;Bott, Matthew J.
• 通讯作者: Bott, Matthew J.