肿瘤特异性 pro-IL-12 激活预先存在的细胞毒性 T 细胞以控制已形成的肿瘤

It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. Interleukin-12 (IL-12) can potently activate lymphocytes, but its clinical use is limited by its short half-life and dose-related toxicity.

In this study, we developed a tumor-conditional IL-12 (pro-IL-12), which masked IL-12 with selective extracellular receptor–binding domains of the IL-12 receptor while preferentially and persistently activating TILs after being unmasked by matrix metalloproteinases expressed by tumors. Systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors compared with IL-12-Fc.

Mechanistically, antitumor responses induced by pro-IL-12 were dependent on TILs and IFNγ.

Furthermore, direct binding of IL-12 to IL-12R on CD8 + , not CD4 + , T cells was essential for maximal effectiveness. Pro-IL-12 improved the efficacy of both immune checkpoint blockade and targeted therapy when used in combination.

Therefore, our study demonstrated that pro-IL-12 could rejuvenate TILs, which then combined with current treatment modalities while limiting adverse effects for treating established tumors.