A Homing System Targets Therapeutic T-cells to Brain Cancer

Successful T-cell immunotherapy for brain cancer should adequately access tumor tissues, but strategies to achieve this have been elusive. We discovered that, in contrast to inflammatory brain diseases, such as multiple sclerosis, where endothelial-cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer-endothelium downregulates these molecules to evade immune-recognition. In contrast, we found that cancer-endothelium upregulates ALCAM, which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted Homing System (HS). We re-engineered ALCAM’s natural ligand, CD6, in a manner that triggers initial anchorage of T-cells to ALCAM and conditionally mediates a secondary-wave of adhesion by sensitizing T-cells to low-level ICAM1 on the cancer-endothelium, thereby creating the adhesion forces necessary to capture T-cells from the bloodstream. Cytotoxic HS T-cells robustly infiltrated brain cancers after intravenous-injection and exhibited potent antitumor activity. We here describe a first-in-class molecule that targets the delivery of T-cells to brain cancer.