Optical tracer history.
Over the last decade, the developments in optical tracers for image-guided surgery, pathology and endoscopy have focused on improving disease specificity through receptor-targeted tracers or so-called smart-activatable fluorescent agents based on the activation of enzymes. The receptor-targeted agents specifically recognize membrane-bound biomarkers overexpressed on the tumor cells (e.g. EGFR, folate receptor-α, CEA, EpCAM, c-MET, CA-IX) or stroma (e.g. VEGF, αvβ3, uPAR), as is the case with targeted immunotherapy. These tracers are developed and evaluated based on the concept of using ‘drugs as imaging agents’ (Scheuer et al Sci Transl Med 2012) and the microdosing concept, thereby lowering the bar for clinical introduction and development. Moreover, this concept has paved the way for using optical molecular imaging in drug development, one of the Services within TRACER.
First in-human study.
In 2011, a pioneering first-in-human study by van Dam et al (Nature Medicine 2011) demonstrated the feasibility of visualizing ovarian cancer tumor deposits with fluorescein-isothiocyanate (FITC)-labeled folate during ovarian cancer debulking surgery. Over the last decade, several clinical trials, some of which are still ongoing, have investigated the application of fluorescently-labeled monoclonal antibodies as tracers for a variety of cancer types and clinical applications such as fluorescence-guided surgery, -pathology and -endoscopy.
Future developments in optical tracers.
Smaller targeting agents – incorporating peptides, protein scaffolds, or antibody-fragments – with improved pharmacokinetic properties and specificity, have also been developed and are undergoing evaluation. Finally, during complex surgeries where lesions of interest reside in close proximity to vital structures like nerves (e.g. in head and neck cancers, prostate cancer and locally advanced rectal cancer), highlighting these vital structures could improve the surgeon’s ability to avoid or preserve them. Thus far, direct visualization of nerves with fluorescent agents remains limited to a few preclinically tested nerve-binding fluorophores, fluorescent peptides, and antibodies. Obviously, color-coding tumors and critical structures for simultaneous viewing will require multi-spectral imaging, currently provided by several camera companies in the field.