Towards clinical translation of nanobody-targeted photodynamic therapy

Cancer is a highly heterogeneous disease and, as such, its treatment presents one of the greatest scientific and medical challenges. Mainstream therapeutic options are often accompanied by side effects and have substantial impact on the quality of life of patients. Efforts have been made in the direction towards novel tumor-selective approaches, with the idea to minimize damage to healthy tissues. In this thesis we focus on an approach developed over the last 7 years: nanobody-targeted photodynamic therapy (NB-PDT). This targeted approach makes use of nanobodies (NBs), which are the smallest naturally occurring antigen binding domains. The NBs guide the selective delivery of a photosensitizer to the tumor cells, a molecule that upon local light application leads to the formation of reactive oxygen species and consequent cell death. NB-PDT has so far shown promise in vitro and in orthotopic mouse models using different molecular targets. As the next step, this thesis focuses on positioning NB-PDT one step closer to the clinic. This thesis highlights the value of NBs over monoclonal antibodies to achieve fast and homogenous distribution throughout tumors, presents the potency of NB-PDT in a clinically relevant model consisting of head and neck squamous cell carcinoma organoids, and describes the in vitro steps towards the application of NB-PDT to treat cats with oral squamous cell carcinoma. Furthermore, the first signs of immune stimulation triggered by NB-PDT are presented, suggesting the induction of an antitumor mechanism with great clinical implications.