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.

摘要：单独或在 与现有疗法相结合，已被证明可以显着提高许多人的生存率 癌症，包括三重阴性乳腺癌（TNBC）。但是，只有大约四分之一 患者对治疗的反应，通常是患有编程死亡配体1（PD-L1）阳性的患者 肿瘤，而大多数人会经历严重的药物相关副作用。有效的可能选择 对免疫疗法的反应者受到以下事实的限制：活检是当前的筛查标准 PD-L1表达式，仅在一个时间点提供生物标志物状态的快照，而它是 知道在治疗过程中PD-L1表达可以动态变化。另外，肿瘤血管 诸如灌注，缺氧和血管生成之类的“归一化”指标可以动态变化 在治疗期间，有可能作为治疗效率的早期指标。因此有一个 迫切需要可以纵向量化分子和的非侵入性成像技术 治疗前后的生理预测性肿瘤生物标志物。这样的技术可以 可能从无效的治疗和威胁生命的影响中节省无反应者，也可以 促进对新组合疗法的强大评估，以提高生存并证明有效 较大的患者人数。我们使用时域荧光成像的初步研究表明 在PD- 与正常组织中的非特异性探针相比，L1阳性肿瘤，从而显着改善 与基于荧光强度的成像相比，灵敏度和特异性。此外，时间 域成像允许使用简单检测和定量多荧光团 光谱和寿命对比（多路复用），因此非常适合成像多个分子和 治疗反应的生理参数。该提议的目的是翻译这些强大的 FLT验证层析成像成像作为多重纵向的新工具的好处 在免疫疗法期间监测生物标志物。我们将验证光学读数的准确性 通过与 组织学。以前已经证明了荧光成像的可行性 淋巴结和乳房等器官。因此，验证FLT多路复用 临床前模型是一个基本步骤，将导致有针对性的临床试验评估TD TNBC患者中非侵入性功能免疫疗法筛查的技术。