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) 在多种癌症中得到了有效应用，但只有 部分患者经历了显着的临床反应和生存。临床医生面临的挑战和 研究人员都在研究如何为患者提供最有效、最及时的免疫治疗。来自临床试验 越来越明显的是，单一生物标志物不太可能涵盖疾病的范围和广度。 对 ICT 的临床反应。相反，合并多个生物标志物组，包括药效学 和预测性生物标志物，已成为必需品。但是，可以执行的测试数量 基线和治疗中活检受到活检组织数量的限制，并且有几个缺点 包括肿瘤间和肿瘤内的异质性和采样误差。这些问题更加复杂化 患有转移性疾病和难以到达部位的患者。正电子发射等成像方法 断层扫描 (PET) 能够对全身进行重复评估，并有助于实时量化 药效学作用。此外，近年来放射性药物制剂的按需试剂盒配方 使得 PET 在癌症治疗中得到广泛和常规的临床应用。然而，PET 在引导方面并未得到充分利用。 由于准确报告放射性活度的分子靶向放射性示踪剂的获取有限，信息通信技术 免疫浸润。发生器生产的镓 68 标记放射性药物，以试剂盒配方或其他形式， 在美国和全球范围内越来越多地用作癌症治疗诊断工具，但尚未有报道 重点是推进信息通信技术的发展。我们的项目满足了对非侵入性生物标志物的需求，以指导 ICT 目标是开发、翻译和传播用于测量程序性死亡的放射性药物 配体 1 (PDL1)。我们将开发一种用于测量 PDL1 的肽基镓 68 标记放射性药物 水平来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，我们将创建一个小瓶 该药剂的试剂盒配方，以方便放射性药物的制备和传播。我们的 放射性示踪剂是肽衍生的，能够测量任何 PD(L)-1 的药效作用 60 分钟内进行原位治疗。我们期望所提出的方法将成为 ICT 的宝贵补充，尤其是 作为非侵入性生物标志物。产生的结果将使临床管理取得根本性进步 患者接受 ICT 治疗，并与行业密切合作，着眼于传播 和广泛的访问。

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.