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

放射免疫基因组栖息地表型预测非小细胞肺癌新辅助免疫疗法的疗效

• 批准号: 10685447
• 负责人: Tina Cascone
• 金额: $ 65.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685447
• 关键词: Address; Adjuvant; Adjuvant Study; Adjuvant Therapy; Algorithms; Biological; Biological Markers; Cancer Etiology; Characteristics; Clinical; Clinical Trials; Clinical effectiveness; Control Groups; Curative Surgery; Data; Data Science; Data Set; Development; Disease; Disease Progression; Evaluation; Evolution; Goals; Habitats; Image; Immune; Immune checkpoint inhibitor; Immuno-Chemotherapy; Immunocompetent; Immunogenomics; Immunologic Memory; Immunologics; Immunotherapy; Knowledge; Lead; Lung; Lymph Node Involvement; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Meta-Analysis; Metastatic Neoplasm to the Lung; Micrometastasis; Modeling; Mus; Neoadjuvant Study; Neoadjuvant Therapy; Neoplasm Metastasis; Nodal; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; PET/CT scan; Pathologic; Patient Care; Patients; Performance; Phase; Phenotype; Physiological; Positioning Attribute; Positron-Emission Tomography; Postoperative Period; Pre-Clinical Model; Primary Neoplasm; Radio; Radiogenomics; Randomized; Recurrent tumor; Reporting; Resectable; Risk; Role; Spatial Distribution; Structure of parenchyma of lung; Surrogate Endpoint; Testing; Thoracic Oncology; Tissues; Toxic effect; Training; Translating; Treatment Efficacy; Tumor Tissue; Tumor-infiltrating immune cells; United States; Unresectable; X-Ray Computed Tomography; biomarker validation; cancer immunobiology; clinical efficacy; clinical investigation; clinical practice; clinical predictors; clinically relevant; cohort; comparative efficacy; computational pipelines; computerized tools; design; disorder risk; efficacy evaluation; fluorodeoxyglucose positron emission tomography; imaging biomarker; immunotherapy trials; improved outcome; lymph nodes; molecular marker; mortality; mouse model; multiple omics; novel; novel therapeutics; patient stratification; peripheral blood; personalized management; phase 2 study; pre-clinical; predictive modeling; prevent; quantitative imaging; radiological imaging; radiomics; randomized trial; research clinical testing; response; serial imaging; standard of care; survival outcome; treatment response; treatment stratification; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions

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.

抽象的 肺癌是美国和全世界癌症相关死亡的主要原因。功效 免疫检查点抑制剂（ICIs）治疗转移性非小细胞肺癌（NSCLC）提示 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（新辅助）而不是术后（辅助）施用 ICI 时，包括 有机会在治疗过程的早期解决微转移，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 可以减少肺转移，增强肿瘤的免疫浸润，并且 与接受单一疗法或辅助联合 ICI 治疗的小鼠相比，总生存期更长。那些结果 通报了第一个报告的随机 2 期研究，测试新辅助 ICI 组合在患有以下疾病的患者中的应用： 使用主要病理缓解（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具有高度 有望用于可切除的非小细胞肺癌，目前正在一项针对患者的 3 期随机研究中进行测试 患有可手术的 NSCLC（CheckMate-77T，主要 PI：Cascone）。然而，所有这些的一个主要缺点是 新辅助试验的一个缺点是不存在可用于对患者进行分层的经过验证的生物标志物。因此，许多 这些试验中的患者在手术时未达到 MPR，表明获得的益处有限 来自感应 ICI。通过推迟对可能不会受益的患者进行手术，疾病进展的风险和 消除了预先提供潜在治愈性手术的机会。正在进行的分子评估 ICI 临床获益的生物标志物已被证明令人失望，如显着的试验间变异性所证明的那样， 可能与瘤内异质性有关。相比之下，放射成像提供了肿瘤的整体视图 特征以及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 率先采取放射照相和放射基因组学策略来解决这一未满足的临床需求。我们假设 成像表型反映了肿瘤微环境，定量成像表型分析将有助于我们了解肿瘤微环境。 了解 ICI 的反应机制并产生临床疗效的替代指标。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并行评估 开发新的成像生物标志物并验证其临床和生物学相关性。本提案的强度 我们的跨学科团队拥有必要的专业知识和能力来治疗患者、获取和分析高 质量、纵向成像和生物样本，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）识别那些最有可能出现这种情况的患者 从新辅助 ICI 中受益，2) 最大限度地提高临床疗效，3) 促进新疗法的开发 治疗将改善更多可切除非小细胞肺癌患者的预后。