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.