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

摘要 肺癌是美国和全世界癌症相关死亡率的主要原因。的疗效 免疫检查点抑制剂（ICI）在转移性非小细胞肺癌（NSCLC）患者中的应用促使 这些药物在早期可手术环境中的临床研究。存在几个理论优势 当我们在术前（新辅助）而不是术后（辅助）给予ICI时， 在治疗过程的早期有机会解决微转移，并可能赋予免疫记忆 以防止肿瘤复发。事实上，我们的可切除NSCLC临床前模型的结果表明， 联合新辅助ICI导致肺转移更少，肿瘤的免疫浸润更大， 与用单一疗法或辅助组合ICI治疗的小鼠相比，总存活期更长。这些结果 告知第一个报告的随机化2期研究，在以下患者中测试新辅助ICI组合： 使用主要病理学缓解（MPR，≤10%存活肿瘤）作为替代终点的可切除NSCLC 临床疗效（NEOSTAR，PI：Cascone）。新辅助化学免疫疗法已被证明是高度 有望用于可切除的NSCLC，目前正在患者中进行的一项3期随机研究中进行测试 可手术NSCLC患者（CheckMate-77 T，主要研究者：Cascone）。然而，所有这些的一个主要缺点是， 新辅助治疗试验的一个缺点是，没有经过验证的生物标志物可用于对患者进行分层。因此，许多 这些试验中的患者在手术时未达到MPR，表明获益有限 从诱导ICIs。通过延迟可能不会受益的患者的手术， 消除了预先提供潜在的治愈性手术的机会。正在进行的分子生物学评价 对ICI临床有益的生物标志物已被证明是令人失望的，如显著的试验间变异性所证明的， 可能与肿瘤内异质性有关。相比之下，放射成像提供了肿瘤的整体视图 特征和与邻近组织的相互作用。基于我们有希望的初步数据，我们建议 放射学和放射基因组学策略，以解决这一未满足的临床需求。我们假设 成像表型反映肿瘤微环境，定量成像表型将揭示我们的 了解对ICI的反应机制，并产生临床疗效的替代品。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策划的数据进行平行评估， 开发新的成像生物标志物并验证其临床和生物学相关性。这个提议的力量 是我们的跨学科团队，具有必要的专业知识和能力来治疗患者，获得和分析高- 质量，纵向成像和生物标本，并快速评估推定的成像生物标志物，用于治疗 反应和临床结果。成像生物标志物的出现将：1）识别那些最有可能 受益于新辅助ICI，2）最大限度地提高临床有效性，3）导致新的 这些治疗将改善更多可切除NSCLC患者的结局。

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.