Radioimmunogenomic Habitat Phenotypes to Predict Efficacy of Neoadjuvant Immunotherapies in Non-Small Cell Lung Cancer

摘要 肺癌是美国和世界范围内与癌症相关的死亡的主要原因。的功效。 免疫检查点抑制物(ICIS)在转移性非小细胞肺癌患者中的作用 这些药物在早期可手术环境中的临床研究。存在几个理论上的优势 当我们在手术前(新佐剂)而不是术后(佐剂)使用ICIS时，包括 在治疗过程中早期处理微转移的机会，并可能传授免疫记忆 以防止肿瘤复发。事实上，我们的可切除非小细胞肺癌临床前模型的结果表明 联合新辅助ICIS可减少肺转移，增加肿瘤的免疫渗透，以及 与单一治疗或佐剂联合ICIS治疗的小鼠相比，小鼠的总体存活时间更长。那些结果 通知了第一个报告的随机第二阶段研究，测试新辅助ICI联合治疗 使用主要病理反应(MPR，≤10%存活肿瘤)作为替代终点的可切除非小细胞肺癌 临床疗效(Neostar，PI：Casone)。新辅助化疗免疫疗法已经被证明是高度有效的。 对于可切除的非小细胞肺癌很有希望，目前正在对患者进行3期随机研究之一进行测试 可操作的非小细胞肺癌(CHECKMate-77T，PI导联：卡斯康)。然而，所有这些产品的一个主要缺点是 新辅助试验，是没有有效的生物标志物存在，可以用来对患者进行分层。因此，许多人 在这些试验中，这些患者中有一半在手术时没有达到MPR，这表明可能获得的好处有限 来自诱导性ICIS。通过推迟那些可能得不到好处的患者的手术，疾病进展和 预先提供潜在治愈手术的机会就会消失。正在进行的分子生物学评价 临床有益于ICIS的生物标志物已被证明令人失望，这一点从显著的试验间变异性中可见一斑。 可能与肿瘤内的异质性有关。相比之下，放射成像提供了肿瘤的整体图像。 特征及其与邻近组织的相互作用。基于我们充满希望的初步数据，我们建议 领先的放射照相和放射基因组学战略，以解决这一未得到满足的临床需求。我们假设 成像表型反映了肿瘤的微环境，而定量成像表型将为我们的 了解ICIS的反应机制和产生临床疗效的替代物。我们将利用 对来自独特临床试验和免疫活性小鼠模型的精心挑选的数据进行平行评估，以 开发新的成像生物标记物，并验证其临床和生物学相关性。这项提议的力量 我们的跨学科团队是否具备必要的专业知识和能力来治疗患者、获取和分析高 质量、纵向成像和生物显微镜，并快速评估用于治疗的假定成像生物标志物 反应和临床结果。成像生物标志物的出现将：1)确定哪些患者最有可能 受益于新佐剂ICIS，2)最大限度地发挥临床疗效，3)导致新的 这些治疗将改善更多可切除的非小细胞肺癌患者的预后。

ABSTRACT Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. The efficacy of immune checkpoint inhibitors (ICIs) in patients with metastatic non-small lung cancer (NSCLC) prompted the clinical investigation of these agents in the early-stage operable setting. Several theoretical advantages exist when we administer ICIs before surgery (neoadjuvant) rather than postoperatively (adjuvant), including an opportunity to address micrometastases early in the course of treatment, and may impart immunologic memory to prevent tumor recurrence. Indeed, the results from our preclinical models of resectable NSCLC demonstrated that combined neoadjuvant ICIs resulted in fewer lung metastases, greater immune infiltration of tumors, and longer overall survival compared with mice treated with monotherapy or adjuvant combined ICIs. Those results informed the first reported randomized phase 2 study testing neoadjuvant ICI combinations in patients with resectable NSCLC using major pathologic response (MPR, ≤10% viable tumor) as a surrogate endpoint for clinical efficacy (NEOSTAR, PI: Cascone). Neoadjuvant chemoimmunotherapy has been shown to be highly promising for resectable NSCLC, and is now being tested in one of the phase 3 randomized studies in patients with operable NSCLC (CheckMate-77T, Lead PI: Cascone). However, a major shortcoming of all of the neoadjuvant trials, is that no validated biomarker exists that can be used to stratify patients. Consequently, many of these patients on these trials do not achieve an MPR at surgery, indicating that limited benefit may be gained from induction ICIs. By delaying surgery in patients who may not benefit, the risks of disease progression and of eliminating a chance to offer potentially curative surgery upfront occur. The ongoing evaluation of molecular biomarkers of clinical benefit to ICIs has proved disappointing as evidenced by the significant intertrial variability, possibly related to intratumor heterogeneity. By contrast, radiologic imaging provides a holistic view of tumor characteristics and interactions with the adjacent tissue. Built on our promising preliminary data, we propose to spearhead radiographic and radiogenomics strategies to address this unmet clinical need. We hypothesize that imaging phenotypes reflect tumor microenvironment, and quantitative imaging phenotyping will shed light on our understanding of the mechanisms of response to ICIs and yield surrogates of clinical efficacy. We will leverage the parallel assessment of well-curated data from unique clinical trials and immunocompetent mouse models to develop new imaging biomarkers and validate their clinical and biological relevance. The strength of this proposal is our interdisciplinary team with the requisite expertise and ability to treat patients, obtain and analyze high- quality, longitudinal imaging and biospecimens and rapidly evaluate putative imaging biomarkers for therapeutic response and clinical outcomes. The advent of imaging biomarkers will: 1) identify those patients most likely to benefit from neoadjuvant ICIs, 2) maximize the clinical effectiveness, and 3) lead to the development of new therapies that will improve outcomes for a greater number of patients with resectable NSCLC.