In mouse models of PDAC, radiation therapy (RT) plus PD1–IL2v (a bispecific that blocks PD-1 and activates IL-2β/IL-2γ, but not IL-2α on Tregs) induced durable local and systemic antitumor immunity marked by transcriptionally and metabolically active antigen-specific CD8+ T cells and enhanced T cell polyfunctionality, activation, and immune memory across tumors, lymph nodes, and blood. It also increased and activated systemic NK cells and reduced the number and function of tumor Tregs. The addition of anti-CD25 blunted immunity due to elimination of an active CD25+ CD8+ T cell population. In patients with PDAC, RT responders upregulated the molecular targets of PD1–IL2v.
Contributed by Lauren Hitchings
ABSTRACT: 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 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.
Author Info: (1) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (2) Department of Radiation Oncology, University of Colorado, Anschutz
Author Info: (1) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (2) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (3) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Microbiology and Immunology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (4) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (5) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (6) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (7) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (8) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (9) Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. (10) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (11) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (12) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (13) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (14) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (15) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (16) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (17) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (18) Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (19) Department of Microbiology and Immunology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. (20) Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. (21) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (22) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (23) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (24) Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (25) Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. (26) Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Microbiology and Immunology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: sana.karam@cuanschutz.edu.
