Simultaneous targeting of PD-1 and IL2RBY with radiation therapy to inhibit pancreatic cancer growth and metastasis

In patients with pancreatic ductal adenocarcinoma (PDAC), we show that response to radiation therapy (RT) is characterized by increased IL2R and IL2R expression, decreased ILR2 and exhaustion markers. The bispecific PD-1-targeted IL-2 variant (IL2v) immunocytokine with engineered IL-2 cis-targeted to PD-1 and abolished IL2R binding targets the activation of tumor-antigen specific T cells while rescuing them from Treg suppression. Using aPD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival along with profound increase in tumor-infiltrating polyfunctional 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, aPD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8 T cells, T cell stemness, tumor-specific memory immune response, NK cell activation, and decreased Tregs. These data show that the novel aPD1-IL2v, leads to profound local and distant response in PDAC.