Abstract B107: Peptide-delivered low dose IL-2 reprograms pancreatic cancer immunity to improve survival
In Hwan Park, Gregory Botta, Shawn Abeynaike, Jonathan Cho, Ashley Martinez, Tridu Huyhn, Daisuke Nishizaki, Charles JurisagaAbstract
Background:
Metastatic pancreatic cancer (PC) has a dismal 5-year survival rate of 2% due to limited chemotherapy, lack of immunotherapy options, and high drug resistance. The tumor-immune microenvironment (TIME) in PC, marked by dense desmoplasia, inactive anti-cancer T-cells, and immunosuppressive regulatory T-cells (Tregs), hinders immunotherapy responses. Novel approaches are needed to overcome these barriers and activate anti-tumor T-cell responses. Interleukin-2 (IL-2), a dual-function cytokine, promotes T-cell proliferation at high doses but induces immunosuppression at low doses. High-dose IL-2 enhances cytotoxic T-cell activity and suppresses Tregs, but its severe toxicities, including capillary leak syndrome (CLS), limit its use. To address these challenges, iRGD—a tumor-targeting CendR peptide currently in Phase 2 trials for metastatic pancreatic cancer—enhances chemotherapy delivery by binding tumor-specific integrins and NRP-1. We hypothesized that iRGD could similarly deliver low-dose (LD) IL-2 into pancreatic tumors, concentrating it within the tumor microenvironment to activate CD8+ T cells, suppress tumor growth, and improve survival while minimizing systemic toxicity.
Results:
In orthotopic KPC mouse models, iRGD combined with LD IL-2 significantly reduced tumor burden and improved survival compared to IL-2 alone, while avoiding systemic toxicities such as capillary leak syndrome and cachexia. Our studies revealed that the combination treatment selectively enhanced CD8+ T cell cytotoxic function, evidenced by increased STAT5 phosphorylation, Granzyme B release, and Caspase-3– mediated apoptosis, without broadly expanding CD4+ T cells or Tregs. The therapeutic effect was abrogated by CD8 depletion, confirming its dependence on cytotoxic T cell activity. Patient-derived PDAC slice cultures further validated increased cytotoxic responses with Certepetide + IL-2 treatment.
Conclusion:
iRGD-guided delivery of low-dose IL-2 reprograms the tumor immune microenvironment, enhancing anti-tumor immunity while mitigating systemic toxicity. This strategy represents a promising translational approach for pancreatic cancer immunotherapy.
Citation Format:
In Hwan Park, Gregory Botta, Shawn Abeynaike, Jonathan Cho, Ashley Martinez, Tridu Huyhn, Daisuke Nishizaki, Charles Jurisaga. Peptide-delivered low dose IL-2 reprograms pancreatic cancer immunity to improve survival [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B107.