71 PD-1/PD-L1 PET imaging: A novel tool to optimize immunotherapy? In Vivo Molecular Imaging In vivo molecular imaging requires radiolabeling of a compound of interest using a radionuclide that matches the compounds size and half-life, followed by visualization with Single Photon Emission computed tomography (SPECT) or PET imaging45. We describe the current status of preclinical and clinical PD-1/PD-L1 imaging studies and discuss major challenges in analyzing and interpreting their results. Preclinical programmed cell death-1/programmed cell death ligand-1 imaging studies Several preclinical studies have demonstrated the feasibility of radionuclide imaging to noninvasively assess PD-1/PD-L1 expression. In preclinical studies, tracers can be directed against human PD-1/ PD-L1 to validate tracers for subsequent clinical use. These tracers are evaluated in immune deficient mice bearing human xenografts or in humanized mice models; mice transplanted with human immune cells. Other tracers are directed against murine PD-1/PD-L1 to investigate the distribution of these agents in animals with a fully functioning immune system. Both strategies have provided valuable information about the potential role of PD-1/PD-L1 imaging to better understand and predict the efficacy of ICI. Different tracer molecules have been developed to image PD-L1 and PD-1. Radiolabeled PD-L1 antibodies can distinguish tumors with different PD-L1 expression levels and allow for monitoring of therapy-induced changes in PD-L1 expression in preclinical tumor models42-22.46. For example, Hettich and colleagues43 developed a copper-64 (64Cu) labeled anti-mouse PD-1 antibody to image PD-1 positive cells in murine tumor models, demonstrating specific tracer uptake in lymphoid organs (lymph nodes and spleen). In the same model, 64Cu-labeled anti-PD-1 PET was able to measure the infiltration of PD-1 positive cells in melanoma lesions in mice that were treated with a combination of radiotherapy and CTLA-4/PDL1 inhibitors, suggesting that PD-1 PET might be used for ICI treatment monitoring. In another study, the clinically approved PD-1 inhibitor pembrolizumab labeled with zirconium-89 (89Zr) was evaluated, demonstrating its potential to image tumor infiltration of adoptively transferred human peripheral blood mononuclear cells in humanized mice engrafted with melanoma tumors47. Next to these studies, several other radiolabeled antibodies, nanobodies, and affibody molecules have preclinically demonstrated to be excellent tracers for noninvasive imaging of PD-L1 and PD-141,18,49. Clinical programmed cell death-1/programmed cell death ligand-1 imaging studies Most clinical PD-1/PD-L1 imaging studies use 89Zr-labeled monoclonal antibodies, which combine the sensitivity of PET with the specificity of the antibody, resulting in whole-body PET imaging in a sensitive and quantitative manner40,45,50,51. Recently, Bensch and colleagues52 reported the first clinical PD-L1 PET imaging study with 89Zrlabeled anti-PD-L1 monoclonal antibody atezolizumab in 22 patients with either locally advanced or metastatic bladder cancer, NSCLC, or triple negative breast cancer. Patients received 10 4
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