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

基本信息

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
项目类别：
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

项目摘要

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。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一些理论优势。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 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联合 ICI 治疗的小鼠相比，总体生存期更长。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）已被证明是高度的。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然而，对于可手术的 NSCLC（CheckMate-77T，主要 PI：Cascone）来说，这是所有这些的一个主要缺点。新辅助试验的一个问题是，不存在可用于对许多测试患者进行分层的经过验证的生物标志物。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通过延迟对可能不会受益的患者进行手术，可以减少疾病进展和风险。正在进行的分子评估消除了预先提供潜在治愈性手术的机会。 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。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。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。我们将利用对 ICI 反应机制和临床疗效替代物的了解。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。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。