Reverting tumor microenvironment into hostile neighborhood by Padeliporfin-ImPACT (TOOKAD VTP) provides high cure rate of urothelial cancers and the ground for clinical treatment of other solid tumors.

A new treatment approach for urothelial cancers (UCa) is described in the preclinical and clinical settings. In brief, the friendly tumor microenvironment (TME) is selectively diverted into a massive generator of deleterious reactive nitrogen species (RNS) by vascular targeted photodynamic therapy (VTP) with WST11 (padeliporfin, TOOKAD). Light induced oxygen radical generation in the tumor circulation, is accompanied by Instantaneous hypoxia, ten-fold amplification of nitric oxide synthase expression by eNOS and iNOS and release of nitric oxide. Nitrotyrozination of the tumor endothelium, followed by vascular permeabilization and collapse initiates self-propagating paraptosis that culminates in coagulative necrosis of the entire tumor within few hours. Concomitant release of danger associated molecular patterns (DAMP) alarms the innate immunity. Massive infiltration of cytotoxic lymphocytes through the broken endothelial barrier accomplishes the local tumor eradication and initiate prolonged adaptive immunity. Differences in the nitric oxide synthase expression within the TME and surrounding normal tissue underscore the selective tumor eradication in animals and human alike. Based on the phase I clinical results, WST11-VTP, renamed Padelliporfin ImPACT (Immune PhotoActivated Cancer Therapy), has gained fast tract approval and orphan drug status for phase III clinical trials on patients with upper tract urothelial cancer.