{Reference Type}: Journal Article
{Title}: Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.
{Author}: Shi W;Liu N;Liu Z;Yang Y;Zeng Q;Wang Y;Song L;Hu F;Fu J;Chen J;Wu M;Zhou L;Zhu F;Gong L;Zhu J;Jiang L;Lu H;
{Journal}: Cell Rep Med
{Volume}: 5
{Issue}: 5
{Year}: 2024 May 21
{Factor}: 16.988
{DOI}: 10.1016/j.xcrm.2024.101531
{Abstract}: The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8+ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.