DNA damaging therapy and immune response in small cell lung cancer subtypes

项目摘要 小细胞肺癌（SCLC）是一种高度侵袭性的疾病，其治疗仍然是一个关键的需求 提供持久的益处和生物标志物来指导治疗选择。虽然免疫疗法提供了临床 目前的化疗-免疫治疗组合对某些患者的总生存期有益， 患者群体仅保持约12个月。小细胞肺癌的一个特别未充分研究的特征是治疗性的 方法来增强免疫介导的反应，这种主要是免疫“冷”癌症。我们集团 以前确定的有希望的药物靶点，增强免疫治疗反应的策略，以及候选药物。 SCLC的预测性生物标志物（包括PARP和其他DNA损伤反应抑制剂， 与免疫疗法组合）。这些都已迅速转化为临床试验。解决当前 研究差距（在NCI的SCLC进展工作组报告中概述），包括（1）调查 SCLC微环境（包括免疫治疗的潜力和局限性），（2）肿瘤异质性，（3） 纵向患者样本的表征，（4）新鉴定亚型的模型，和（5） 基于血液的生物标志物方法，我们组建了一个多学科团队，科学，临床， 在SCLC和癌症免疫学领域的翻译和计算专业知识。连同我们 胸科生物信息学工作组，我们最近发现，有四个不同的，基于表达 SCLC的分子亚群，包括新的“发炎”亚型（Gay等人，Cancer Cell，2021）。重要的是， 这些SCLC亚型（SCLC-ASCLC、NEUROD 1、POU 2F 3和SCLC-炎症）具有不同的治疗效果， 可以利用这些漏洞来加强对国际竞争性断路器组合的反应。我们生成并分析了 来自活检组织和循环肿瘤细胞（“CDX”）的新的患者来源的异种移植物模型代表了主要的 SCLC亚型。这些，再加上一个已建立的人源化小鼠模型系统，将使我们能够深入研究 表征对ICB和DNA损伤疗法的组合的免疫应答机制。基于 根据我们的数据，我们假设SCLC亚型和SLFN 11状态将决定不同的免疫介导的 对DNA损伤疗法和ICB的反应，并且靶向复制应激的新组合可以 增强免疫“冷”SCLC中的ICB应答。为了解决这些假设，在目标1中，我们将确定 DNA损伤疗法对SCLC分子亚型特异性免疫调节作用的联合临床试验 治疗前后的体内和患者标本中。在目标2中，我们将研究癌细胞SLFN 11作为一种肿瘤细胞。 预测性生物标志物及其在STING途径活化和抗肿瘤免疫中的作用。在目标3中，我们将 评估克服耐药性的方法，包括与ICB联合使用的替代DNA损伤剂。的 总体假设是，SCLC肿瘤的分子亚型，与增强免疫治疗的策略相结合， 反应，将通过提供个性化的，生物标志物知情的方法来提高SCLC患者的生存率 接受治疗

PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly aggressive disease for which there remains a critical need for therapies that provide durable benefit and biomarkers to guide treatment selection. While immunotherapy provides clinical benefit for some patients, overall survival with current chemotherapy-immunotherapy combinations in unselected patient populations remains only ~12 months. A particularly understudied feature of SCLC is therapeutic approaches to enhance immune-mediated responses for this largely immune “cold” cancer. Our group has previously identified promising drug targets, strategies to enhance immunotherapy response, and candidate predictive biomarkers for SCLC (including PARP and other DNA damage response inhibitors alone an in combination with immunotherapy). These have been rapidly translated into clinical trials. To address current research gaps (outlined in the NCI’s SCLC Progress Working Group report), including (1) investigation of the SCLC microenvironment (including the potential and limitations of immunotherapy), (2) tumor heterogeneity, (3) characterization of longitudinal patient samples, (4) models of newly identified subtypes, and (5) development of blood-based biomarker approaches, we have assembled a multidisciplinary team with scientific, clinical, translational, and computational expertise in the field of SCLC and cancer immunology. Together with our Thoracic Bioinformatics Working Group, we recently found that there are four distinct, expression-based molecular subsets of SCLC, including a novel “Inflamed” subtype (Gay et al, Cancer Cell, 2021). Importantly, these SCLC subtypes (SCLC-ASCLC, NEUROD1, POU2F3, and SCLC-Inflamed) have distinct therapeutic vulnerabilities that can be leveraged to enhance response to ICB combinations. We have generated and profiled new patient-derived xenograft models from biopsies and circulating tumor cells (“CDXs”) representing the major SCLC subtypes. These, together with an established humanized mouse model system, will enable us to deeply characterize mechanisms of immune response to combinations of ICB and DNA damaging therapies. Based on our data, we hypothesize that SCLC subtypes and SLFN11 status will determine distinct, immune mediated responses to DNA damaging therapies and ICB and that novel combinations targeting replication stress may enhance ICB response in immune “cold” SCLC. To address these hypotheses, in Aim 1, we will determine the SCLC molecular subtype-specific immune modulatory effects of DNA damaging therapy in co-clinical trials in vivo and in patient specimens before and after treatment. In Aim 2, we will investigate cancer cell SLFN11 as a predictive biomarker and its role in STING pathway activation and anti-tumor immunity. Lastly, in Aim 3, we will assess methods to overcome resistance, including alternative DNA damaging agents combined with ICB. The overall hypothesis is that molecular subtyping of SCLC tumors, paired with strategies to enhance immunotherapy response, will improve survival for patients with SCLC by providing a personalized, biomarker-informed approach to therapy.