Clinical translation of a PD-L1 PET tracer to optimize immune checkpoint therapy in patients with non-small cell lung cancers

项目摘要。 尽管免疫检查点疗法（ICT）在广泛的癌症中有效应用，但只有一种免疫检查点疗法（ICT）可以治疗癌症。 一部分患者经历了显著的临床反应和存活。临床医生面临的挑战， 研究人员一致认为，如何为患者提供最有效和最及时的免疫疗法。进行临床试验 越来越明显的是，单一的生物标志物不太可能捕捉的范围和广度， 对ICT的临床反应。相反，纳入多个生物标志物组，包括药效学 和预测性生物标志物，已经成为一种必需品。但是，可以使用 基线和治疗中的活组织检查受到活组织检查组织量的限制，并且具有几个缺点 包括肿瘤间和肿瘤内的异质性和取样误差。这些问题在以下方面变得更加复杂： 转移性疾病和难以进入部位的患者。正电子发射等成像方法 断层扫描（PET）能够重复评估全身，并促进实时定量 药效学效应此外，近年来，放射性药物制剂的按需试剂盒制剂 已经使得PET在癌症护理中的广泛和常规临床使用成为可能。然而，PET在引导 ICT由于有限的获得分子靶向放射性示踪剂，准确报告的活动， 免疫浸润发生器生产的镓-68标记的放射性药物，以试剂盒制剂或其他形式， 在美国和地球仪越来越多地用作癌症的治疗诊断工具，但尚未报道 重点是推进ICT。我们的项目解决了对非侵入性生物标志物的需求， 目标是开发、翻译和传播一种用于测量程序性死亡的放射性药物 配体1（PDL 1）。我们将开发一种基于肽的镓-68标记的放射性药物，用于测量PDL 1 水平，以指导信息通信技术，并在癌症患者中进行首次人体研究。此外，我们将创建一个单一的小瓶 试剂试剂盒制剂以使得能够方便地制备和散布放射性药物。我们 放射性示踪剂是肽衍生的，并且独特地能够测量任何PD（L）-1的药效学效应。 我们预计，所提出的方法将是一个有价值的除了ICT，特别是 作为一种非侵入性生物标志物。产生的结果将使临床管理的根本进步 接受信息和通信技术治疗的病人的信息和通信技术，并与业界密切合作，着眼于传播 广泛的访问。

Project Summary. Despite the efficacious application of immune checkpoint therapy (ICT) across a broad range of cancers, only a subset of patients experience remarkable clinical responses and survival. The challenge facing clinicians and researchers alike is how to deliver the most effective and timely immunotherapy to patients. From clinical trial data it is becoming increasingly evident that a single biomarker is unlikely to capture the scope and breadth of clinical responses to ICT. Rather, incorporation of multiple biomarker panels, including both pharmacodynamic and predictive biomarkers, has become a necessity. However, the number of tests that can be performed with baseline and on-treatment biopsies is limited by the amount of biopsy tissue, and has several shortcomings including inter- and intra-tumoral heterogeneity and sampling errors. Those problems are compounded in patients with metastatic disease and difficult-to-access locations. Imaging methods such as positron emission tomography (PET) enable repetitive evaluation of the whole body and facilitate real-time quantification of pharmacodynamic effects. Also, in recent years on-demand kit formulations of radiopharmaceutical preparations have enabled widespread and routine clinical use of PET in cancer care. However, PET is underutilized in guiding ICT due to the limited access to molecularly targeted radiotracers that accurately report on the activity of the immune infiltrate. Generator-produced Gallium-68-labeled radiopharmaceuticals, in kit formulation or otherwise, are increasingly used in the US and across the globe as theranostic tools for cancer but have not been reported with a focus on advancing ICT. Our project addresses the need for non-invasive biomarkers for guiding ICT with an objective to develop, translate and disseminate a radiopharmaceutical for measuring programmed death ligand 1 (PDL1). We will develop a peptide-based Gallium-68-labeled radiopharmaceutical for measuring PDL1 levels to guide ICT and conduct a first-in-human study in cancer patients. Moreover, we will create a single vial kit formulation of that agent to enable convenient radiopharmaceutical preparation and dissemination. Our radiotracer is peptide-derived and uniquely capable of measuring pharmacodynamic effects of any PD(L)-1 therapeutic in situ in 60 min. We expect that the proposed approach will be a valuable addition to ICT, especially as a non-invasive biomarker. The results generated will enable a fundamental advance in clinical management of patients undergoing ICT and carried out in close partnership with industry with an eye towards dissemination and broad access.