Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy to inhibit pancreatic cancer growth and metastasis

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased ILR2α expression. The bispecific, PD1-IL2v, is a PD-1-targeted IL-2 variant (IL2v) immunocytokine with engineered IL-2 cis-targeted to PD-1 and abolished IL-2Rα 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 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. Piper and Hoen et. al show that combination of radiation and PD1-IL2v immunotherapy enhances CD8 + T cell polyfunctionality, activation, and immune memory across tumor, lymph node, and blood compartments and results in a durable local and systemic anti-tumor response.