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

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（Matthew Bott）博士领导，他是该院胸外科服务的初级教员 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。

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.