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: 10278410
• 负责人: Tina Cascone
• 金额: $ 62.45万
• 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/10278410
• 关键词: Address; Adjuvant; Adjuvant Therapy; Algorithms; Biological; Biological Markers; Cancer Etiology; Characteristics; Clinical; Clinical Trials; Clinical effectiveness; Control Groups; Curative Surgery; Data; Data Science; Data Set; Development; Diagnostic radiologic examination; Disease; Disease Progression; Evaluation; Evolution; Goals; Habitats; Image; Immune; Immune checkpoint inhibitor; Immuno-Chemotherapy; Immunocompetent; Immunogenomics; Immunologic Memory; Immunologics; Immunotherapy; Knowledge; Lead; Light; Lung; 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; Nonmetastatic; 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; Recurrence; Reporting; Resectable; Risk; Role; Spatial Distribution; Structure of parenchyma of lung; Surrogate Endpoint; Testing; Therapy Evaluation; Thoracic Oncology; Tissues; Toxic effect; Training; Translating; Treatment Efficacy; Tumor Tissue; Tumor-infiltrating immune cells; United States; Unresectable; base; cancer immunobiology; clinical efficacy; clinical investigation; clinical practice; clinical predictors; clinically relevant; cohort; comparative efficacy; computational pipelines; computerized tools; contrast imaging; design; efficacy evaluation; fluorodeoxyglucose positron emission tomography; imaging biomarker; 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; 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 肺癌是美国和全球与癌症相关死亡率的主要原因。效率 转移性非小肺癌（NSCLC）患者的免疫检查点抑制剂（ICI）促使 在早期可操作环境中对这些药物的临床研究。存在一些理论上的优势 当我们在手术前进行ICI（新辅助）而不是正面（辅助），包括 在治疗过程中早期解决微型转移的机会，并可能传授免疫记忆 预防肿瘤复发。实际上，我们可切除的NSCLC临床前模型的结果证明了 新辅助ICIS的结合导致肺转移较少，肿瘤的免疫浸润更大，并且 与用单一疗法或调整ICIS合并的小鼠相比，总体存活率更长。这些结果 告知第一个报告的2期随机研究测试测试新辅助ICI组合的患者 可切除的NSCLC使用主要的病理反应（MPR，≤10％可行肿瘤）作为替代端点 临床效率（Neostar，PI：Cascone）。新辅助化学免疫性疗法已被证明是高度的 有望切除NSCLC，现在正在患者的3期随机研究之一中进行测试 使用可操作的NSCLC（Checkmate-77T，Lead Pi：Cascone）。但是，所有的主要缺点 NeoAdjuvant试验是，不存在可用于对患者进行分层的验证生物标志物。因此，许多 在这些试验中的这些患者中，手术没有达到MPR，表明可能会获得有限的收益 来自感应ICIS。通过延迟可能无法受益的患者的手术，疾病进展的风险和 消除有机会预先治愈手术的机会。分子的持续评估 事实证明，ICIS临床益处的生物标志物被证明是令人失望的 可能与肿瘤内异质性有关。相比之下，放射学成像提供了肿瘤的整体视图 特征和与相邻组织的相互作用。基于我们承诺的初步数据，我们建议 长矛射线照相和放射基因组学策略，以满足这种未满足的临床需求。我们假设这一点 成像表型反映了肿瘤微环境，定量成像表型将在我们的 理解对ICI的反应机制和临床效率的替代物。我们将利用 从独特的临床试验和免疫功能的小鼠模型到策划的数据的平行评估到 开发新成像生物标志物并验证其临床和生物学相关性。该提议的优势 是我们的跨学科团队，具有必要的专业知识和治疗患者，获得和分析高级的能力 质量，纵向成像和生物测量，并迅速评估假定的成像生物标志物的治疗 反应和临床结果。成像生物标志物的冒险将：1）确定最有可能的患者 受益于新辅助ICIS，2）最大化临床有效性，3）导致新的发展 可以改善更多可切除NSCLC患者的预后疗法。