[18F]4FN PET Imaging of Innate Immunity Activation During Immunotherapy-Induced Adverse Events

ABSTRACT While monoclonal antibodies inhibiting immune checkpoints (ICI) and CAR T-cell therapies have dramatically changed the therapeutic options for many cancer patients, up to 60% of patients will experience immune-related adverse events (irAE) depending on the tumor type and immunotherapy. Thus, many patients treated with immunotherapy will not see long term benefit and therefore only suffer potential side effects (and possibly hyper progression), and the importance of predicting and managing immunotherapy-related adverse events has already been identified as a critical gap in knowledge and clinical practice. Significantly, a common molecular node of integration between the various inflammatory mechanisms of irAE, particularly in the subacute setting, focuses on spurious activation of the innate immune system. Recently, we reported the synthesis and validation of 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical for the selective imaging of high energy oxygen and nitrogen radical species (RONS) by PET/CT. [18F]4FN provides a convenient reagent for rapid, quantitative whole-body imaging to identify and monitor inflammatory foci generated by NADPH oxidase-2 (NOX2) and myeloperoxidase (MPO) of the innate immune system and multi-organ inflammation, including immunotherapy-mediated irAE. Monitoring irAE by PET imaging is the long-term clinical imaging goal of our line of investigation. Near-term, we propose to investigate the role of activated innate immunity in vivo by combined molecular imaging and multiplexed analysis of tissues in mechanism-based pre-clinical murine models of irAE for which we can enhance our understanding of the activation dynamics of innate immunity and gain signals of efficacy.