同时靶向 PD-1 与 IL-2Rβγ 联合放疗抑制胰腺癌生长与转移

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2R and IL-2R along with decreased IL-2R expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2R binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression.

Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8 + T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8 + T cells.

In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8 + T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC.