IL-7-PD-L1 nano-antibody mediated "zipper" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.

Abstract

Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.