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

项目摘要/摘要 肺癌是全国癌症相关死亡的主要原因。在转移性非小细胞肺癌患者中 细胞肺癌，最近的随机试验已经证明联合化疗和 T细胞检查点封锁超过常规治疗。这些研究已经进行了联合化疗 T细胞检查站封锁了肺癌患者的新护理标准。然而， 化学免疫疗法的联合疗效的机制尚不清楚。因此， 药物组合是根据肺癌的历史治疗方案确定的，而不是基于科学原理。 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。这里描述的建议建立在我们之前的工作基础上，即 确定了一种有效地诱导细胞衰老的靶向疗法的组合。除了……之外 显示出持久的生长停滞，这些衰老的细胞分泌一系列促进免疫的细胞因子 监视和清除肿瘤细胞。有趣的是，我们的初步数据表明，类似的衰老状态 可由标准化疗诱导为肺癌。我们假设这种衰老可能 有助于临床观察的化疗和T细胞检查点的联合疗效 封锁。 我们建议对化疗引起的衰老进行特征描述，特别强调分泌型衰老。 免疫调节性细胞因子。我们将利用体外和体内的正交系统来探索相关性 从衰老到适应性免疫监测，目的是确定衰老是否真的 在T细胞检查点抑制的背景下，有助于细胞毒性。此外，我们还将审问肿瘤 接受化疗、免疫检查点阻断或联合治疗的患者的样本 记录化疗引起的非小细胞肺癌患者衰老的相关性。由生成的数据 这项建议将与非小细胞肺癌治疗的现状直接相关，并将促进 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，他是胸外科的初级教员，位于 纪念斯隆·凯特琳癌症中心(MSK)，对肺癌和免疫治疗感兴趣。这个 研究将在国际癌症领先者斯科特·洛博士的共同指导下进行 生物学和Jedd Wolchok博士，他是一位非常有成就的翻译免疫肿瘤学专家。MSK提供了一个 从事基础研究和翻译研究的良好环境。为了实现他成为一名 作为独立研究员，博特博士制定了一套结构化的活动课程，旨在扩大他的 知识基础，扩展他的技能，磨练他的科学探究方法。

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.