One signal activated TIL enables potent anti-tumor activity across solid tumor types

Abstract

AbstractAdoptive T cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) has shown compelling anti-tumor activity across various solid tumors. The function and status of TIL significantly influence its anti-tumor potential. In this study, we present the development of One-Signal-Activated TIL (OSAT), highlighting its robust anti-tumor activity in various syngeneic tumor models. We designed 10 unique signals by integrating CD3Zwith a secondary signaling molecule. From these, we identified a specific signal, denoted as OSAT, which efficiently induces T cell activation when paired with a sole CD3 antibody. Subsequently, we benchmarked delivery approaches for OSAT, through genome editing, lentivirus integration, and plasmid electroporation. We found that electroporation yielded the most potent expression effect among these methods. Further, we demonstrated that OSAT exhibited robust antitumor activity bothin vitroandin vivoacross diverse solid tumors. Finally, we synergized OSAT with PD-1 blockade therapy to achieve a highly effective and enduring anti-tumor impact in cancer immunotherapy, facilitating sustained enhancement of anti-tumor activity.