Simultaneous targeting of PD-1 and IL-2R
Menée à l'aide de lignées cellulaires et de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence l'intérêt, pour supprimer la croissance tumorale et le processus métastatique, d'un traitement combinant une radiothérapie et un anticorps bispécifique ciblant simultanément la protéine PD-1 et les protéines bêta et gamma du récepteur de l'interleukine IL-2
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-2Rα 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-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 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.
Cancer Cell 2023