First-in-Human Imaging of Innate Immunity Activation with a Redox-Tuned PET Reporter

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ABSTRACT While monoclonal antibodies inhibiting immune checkpoints (ICI) are able to restore anti-tumor immunity and 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 ICI. Thus, the majority of patients treated with ICI will not see long term benefit and therefore only suffer potential side effects (and possibly hyper progression), and the importance of predicting and managing ICI-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 imaging setting, focuses on the spurious activation of the innate immune system. In this regard, we recently reported the discovery and validation of 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical for selective imaging of highly oxidizing radicals by PET/CT, thus enabling interrogation of activation of key cells participating in innate immunity. This novel PET radiopharmaceutical may provide a convenient reagent for rapid, whole-body imaging and quantitative non-invasive surveillance of radical-mediated inflammatory foci generated by the innate immune system during ICI-mediated irAE. Monitoring irAE by PET imaging is the long-term clinical imaging goal of this line of investigation. For this R21 proposal, we propose to 1) drive the agent into first-in- human dosimetry and safety studies in a relevant population of patients at MDACC with irAE, and 2) gain preliminary signals of efficacy. If successful, this novel agent may increase the clinical utility of PET in precision medicine.