Photochemical internalisation (PCI) is an intracellular drug delivery technology based on the combination of an endosome and lysosome-targeting photosensitiser (S) that is given together with a drug (D) that also accumulates in the same endocytic vesicles (e.g. due to endocytosis, active transport or protonation in the acidic lumen) which are further transported to late endosomes and lysosomes. During uptake of the therapeutic drug molecules, the amphiphilic PCI photosensitiser becomes incorporated in the membrane of the endocytic vesicles and co-localised with the drug of interest. By a time and space-controlled exposure with light at a wavelength that activates the photosensitiser, reactive oxygen species (ROS) are generated and this results in lipid peroxidation and rupture of the endosomal or lysosomal membrane subsequently inducing cytosolic release of the drug.
Project I: PCI of immunotoxins targeting cancer stem cells
Despite progress in radio-, chemo- and targeting-based therapy of cancer, treatment resistance still remains a major problem for the majority of patients with aggressive tumors. In a high number of research papers during the last two decades it has been suggested that a small population of surviving cancer cells have normal stem-like properties and, hence, they are called cancer stem cells (CSCs). According to the CSC hypothesis, CSCs are suggested to drive and maintain tumor development. CSCs are intrinsically and notoriously resistant to conventional cancer therapies and they are responsible for the tumor recurrence after therapy. By use of the PCI method we have shown that it is possible to target and kill CSCs by light-triggered activation of model antibody-toxin conjugates (both chemical and recombinant) targeting CD133, CD44, EpCAM and CSPG4. In addition, PCI-based photosensitizers are not substrate of efflux pumps such as P-gp (MDR1) or ABCG2, making this approach a rational strategy for the light-controlled elimination of CSCs.
Project II: PCI of cancer stem cell-derived vaccine antigens
Currently, we are also developing the PCI method to enhance the efficacy of cancer vaccines. Entrapment of vaccine peptides in endosomes and lysosomes is major obstacle for therapeutic cancer vaccines. The idea behind this project is to induce endosomal escape of cancer stem cell-derived peptides thereby maximizing antigen-presenting cells possibility to present the antigens via the MHC class I receptor. This way of cross-presentation may lead to a shift from CD4+ helper T-cell activation (MHC class II presentation) to CD8+cytotoxic T-cell lymphocyte activation and thereby to a selective targeting an kill of CSC by the body’s own immune system. Until now, we have in several proof-of-concepts demonstrated that the PCI technology has indeed the capacity to significantly boost the efficacy of model vaccines.
PCI has been demonstrated to be highly efficient in >80 different cancer cell lines and >10 xenograft models using therapeutics including protein toxins, immunotoxins (ITs), chemotherapeutics that for several reasons accumulate in lysosomes, including bleomycin, doxorubicin and mitoxantrone. PCI in combination with bleomycin was found to be tolerable and safe in a Phase I clinical trial, which was published in Lancet Oncology in 2016. Currently, PCI is under evaluation in two different clinical trials: 1) PCI in combination with gemcitabine for the treatment of inoperable bile duct cancer followed by systemic cisplatin/gemcitabine (Clinical identifier: NCT01900158) and 2) PCI of model vaccines (HPV peptides and KLH) in healthy volunteers in the UK (Phase I, Clinical identifier: NCT02947854)