Multiplexed time domain fluorescence tomography of tumor biomarkers during immunotherapy

免疫治疗期间肿瘤生物标志物的多重时域荧光断层扫描

• 批准号: 10372211
• 负责人: Dan Gabriel Duda
• 金额: $ 44.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372211
• 关键词: 4T1; Address; Age of Onset; Antibodies; Behavior; Biological Markers; Biopsy; Blood Vessels; Blood Volume; Breast; Breast Cancer Model; Breast Cancer Patient; Bypass; Clinical; Clinical Trials; Combined Modality Therapy; Data; Detection; Development; Disease; Environment; Evaluation; Fluorescence; Fluorescent Dyes; Goals; Histology; Hypoxia; Image; Imaging Techniques; Immune; Immune system; Immunologic Receptors; Immunotherapy; Interferon Type II; Label; Life; Malignant Neoplasms; Methods; Molecular; Monitor; Mus; Nonionizing Radiation; Normal tissue morphology; Optics; Organ; Paclitaxel; Patients; Perfusion; Pharmaceutical Preparations; Physiological; Positron-Emission Tomography; Pre-Clinical Model; Prognosis; Resistance; Savings; Sensitivity and Specificity; Signal Transduction; Standardization; Survival Rate; Techniques; Technology; Time; Tissues; Translating; Treatment Efficacy; Treatment Protocols; Treatment Side Effects; Tumor Markers; Validation; angiogenesis; antibody conjugate; base; blood perfusion; breast imaging; cancer cell; cancer therapy; chemotherapy; clinically relevant; cost; design; diffuse optical tomography; experience; fluorescence imaging; fluorescence lifetime imaging; fluorophore; improved; in vivo; in vivo Model; ineffective therapies; instrumentation; lymph nodes; molecular imaging; molecular marker; near infrared dye; new combination therapies; non-invasive imaging; non-invasive monitor; novel strategies; optical imaging; patient population; pre-clinical; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; screening; side effect; time use; tomography; tool; treatment response; triple-negative invasive breast carcinoma; tumor; tumor hypoxia; uptake

Abstract: Immunotherapy using programmed death 1 receptor (PD-1) blockade, either alone or in combination with existing therapies, has been proven to significantly improve survival rates for many cancers, including triple negative breast cancer (TNBC). However, only about a quarter of the patients respond to treatment, typically those with programmed death ligand 1 (PD-L1)-positive tumors, while a majority experience serious drug related side effects. The efficient selection of likely responders to immunotherapy is limited by the fact that biopsy, the current screening standard for PD-L1 expression, provides only a snapshot of biomarker status at a single time point, while it is known that PD-L1 expression can dynamically change during therapy. Additionally, tumor vascular “normalization” indicators, such as perfusion, hypoxia and angiogenesis can dynamically change during treatment, potentially serving as early indicators of treatment efficacy. There is therefore an urgent need for non-invasive imaging techniques that can longitudinally quantify molecular and physiological predictive tumor biomarkers before and during treatment. Such techniques can potentially save non-responders from ineffective treatment and life-threatening effects and can also facilitate a robust evaluation of new combination therapies that improve survival and prove effective in a larger patient population. Our preliminary studies using time domain fluorescence imaging indicate that the fluorescence lifetime (FLT) of immune-receptor targeted near infrared probes is longer in PD- L1 positive tumors compared to non-specific probe in normal tissue, thereby dramatically improving sensitivity and specificity compared to fluorescence intensity-based imaging. Furthermore, time domain imaging allows the simultaneous detection and quantification of multiple fluorophores using spectral and lifetime contrast (multiplexing) and is therefore ideal for imaging multiple molecular and physiologic parameters of treatment response. The goal of this proposal is to translate these powerful benefits of FLT to validate tomographic FLT imaging as a new tool for multiplexed longitudinal monitoring of biomarkers during immunotherapy. We will validate the accuracy of the optical readouts for monitoring therapeutic response longitudinally in TNBC-bearing mice by comparison with histology. The feasibility of fluorescence imaging has previously been demonstrated for superficial lymph nodes and for organs such as the breast. Therefore, validation of FLT multiplexing in preclinical models is a fundamental step that will lead to targeted clinical trials to evaluate TD technology for non-invasive functional immunotherapy screening in TNBC patients.

翻译后摘要：免疫治疗使用程序性死亡1受体（PD-1）的封锁，无论是单独或在 与现有的治疗方法相结合，已被证明可以显着提高许多患者的生存率。 癌症，包括三阴性乳腺癌（TNBC）。然而，只有大约四分之一的 对治疗有反应的患者，通常为程序性死亡配体1（PD-L1）阳性患者 肿瘤，而大多数经历严重的药物相关的副作用。可能的有效选择 免疫治疗的应答者受到活检的限制，活检是目前的筛查标准， PD-L1表达仅提供了单个时间点生物标志物状态的快照，而PD-L1表达在 已知PD-L1表达可以在治疗期间动态变化。此外，肿瘤血管 “正常化”指标，如灌注、缺氧和血管生成可以动态变化 在治疗过程中，可能作为治疗效果的早期指标。因此， 迫切需要非侵入性成像技术， 治疗前和治疗期间的生理预测肿瘤生物标志物。这样的技术可以 可能使无应答者免于无效治疗和危及生命的影响， 促进对改善生存率并证明有效的新联合疗法的稳健评估， 更大的患者群体。我们使用时域荧光成像的初步研究表明， 免疫受体靶向近红外探针的荧光寿命（FLT）在PD中更长， 与正常组织中的非特异性探针相比，L1阳性肿瘤，从而显著改善 与基于荧光强度的成像相比，灵敏度和特异性更高。此外，时间 域成像允许同时检测和定量多个荧光团， 光谱和寿命对比度（多路复用），因此是成像多个分子和 治疗反应的生理参数。该提案的目标是将这些强大的 FLT的好处，以验证断层FLT成像作为一种新的工具， 在免疫治疗期间监测生物标志物。我们将验证光学读数的准确性 用于通过与对照组相比，纵向监测携带TNBC的小鼠中的治疗反应。 组织学荧光成像的可行性先前已经被证明用于表面的 淋巴结和器官，如乳房。因此，FLT多路复用在 临床前模型是一个基本步骤，将导致有针对性的临床试验，以评估TD 用于TNBC患者的非侵入性功能性免疫治疗筛选的技术。