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.