Peptide-delivered low dose IL-2 reprograms pancreatic cancer immunity to improve survival

Metastatic pancreatic cancer (PC) has a dismal 5-year survival of only 2% due to limited chemotherapy efficacy, poor drug penetration, and an immunosuppressive TIME. Dense desmoplasia, inactive anti T-cells, and highly enriched immunosuppressive Tregs hinder immunotherapy responses.IL-2, a dual-function cytokine that promotes T-cell growth at high concentrations while also inducing immunosuppression at lower concentrations. High dose (HD) IL-2 is a highly an active immunotherapy that enhances cytotoxic T-cell activity while attenuating suppressive Tregs with cures in melanoma and renal cell carcinoma. Unfortunately, HD IL-2 has significant systemic toxicities that induce capillary leak syndrome (CLS), severe hypotension, and renal failure. The CendR-peptide (iRGD) binds to av/B3 integrins specifically at the tumor and induces a NRP-1 dependent transcytotic uptake of co-administered drug and is currently being evaluated in Phase 2 metastatic PC clinical trials. We hypothesized that iRGD could direct systemically low dose (LD) IL-2 into mouse PC and concentrate it locally within the tumor as HD IL-2. As such, we immunomodulate the TIME of PC to activate CD8 cytotoxic T-cells, reduce tumor growth and increases survival while reducing systemic toxicity associated with HD IL-2.Orthotopic KPC PC were developed in C57BL6 WT mice. Tumor-bearing mice were treated i.v. with iRGD and titrated concentrations of IL-2 (3/week). Tumors were analyzed for CD8+ T-cell proliferation, activation, and cytotoxicity. CD8 T cell depletion confirmed necessity of cytotoxic T cells. Lung tissue was evaluated for IL-2 induced CLS. Patient-derived PDAC slice cultures were treated ex vivo for translational relevance. iRGD + LD IL-2 significantly reduced tumor weight and increased survival compared with monotherapy or HD IL-2. The median survival in treated mice was significantly increased. iRGD combination treatment avoided cachexia, CLS, and systemic inflammation, with no elevation in IL-6 or TNF-a. iRGD combined with LD IL-2 did not reduce Treg numbers or increase CD8 T-cell infiltration/proliferation, but enhanced resident cytotoxic T-cell activity as demonstrated by increased p-STAT5, Granzyme B, and cl-Caspase 3. CD8+ T-cell depletion abrogated these effects, confirming CD8+ T cell dependence. In patient-derived PDAC slice cultures, iRGD+IL-2 increased Granzyme B, supporting translational relevance. Importantly, the peptide combination therapy avoids the severe side effects of CLS and cachexia commonly associated with HD IL-2. This combination significantly improves anti-tumor responses and prolongs survival in preclinical models of mouse and human PC, highlighting a robust, safe, and sustained anti-tumor immune response. iRGD combined with LD IL-2 has appropriate pre-clinical anti-cancer and safety signals to warrant early Phase 1 clinical trials in PC.