Total-body Dynamic Imaging and Kinetic Modeling of18F-AraG in Healthy Individuals and a Non-Small Cell Lung Cancer Patient Undergoing Anti-PD-1 Immunotherapy

Abstract

ABSTRACTImmunotherapies, especially the checkpoint inhibitors such as anti-PD-1 antibodies, have transformed cancer treatment by enhancing immune system’s capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging.18F-AraG is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by non-invasive quantification of immune cell activity within tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of18F-AraG, as a potential quantitative biomarker for immune response evaluation.MethodsThe study consisted of 90-min total-body dynamic scans of four healthy subjects and one non-small cell lung cancer (NSCLC) patient, scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection were employed to analyze tracer kinetics in various organs. Additionally, seven sub-regions of the primary lung tumor and four mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess reliability of kinetic parameter estimation. Correlations of SUVmean, SUVR (tissue-to-blood ratio), and Logan plot slope (KLogan) with total volume-of-distribution (VT) were calculated to identify potential surrogates for kinetic modeling.ResultsStrong correlations were observed betweenKLoganand SUVR values withVT, suggesting that they can be used as promising surrogates forVT, especially in organs with low blood-volume fraction. Moreover, the practical identifiability analysis suggests that the dynamic18F-AraG PET scans could potentially be shortened to 60 minutes, while maintaining quantification accuracy for all organs-of-interest. The study suggests that although18F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response post-therapy. While SUVmean showed variable changes in different sub-regions of the tumor post-therapy, the SUVR,KLogan, andVTshowed consistent increasing trends in all analyzed sub-regions of the tumor with high practical identifiability.ConclusionOur findings highlight the promise of18F-AraG dynamic imaging as a non-invasive biomarker for quantifying the immune response to immunotherapy in cancer patients. The promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.