Abstract 41P
Background
Due to limited cytotoxic chemotherapy, no immunotherapy options, and high drug resistance, metastatic pancreatic cancer (PC) has a dismal 5-year survival of only 2%. The tumor-immune microenvironment in PC, marked by complex, dense desmoplasia, inactive anti-cancer T-cells, and immunosuppressive regulatory T cells, hinders immunotherapy responses. Novel approaches are required to overcome these barriers and activate anti-tumor T-cell responses. Interleukin-2 (IL-2), a dual-function cytokine, promotes T-cell growth at high doses (HD) whereas low doses (LD) cause immunosuppression. HD IL-2 enhances cytotoxic T-cell activity and suppresses Tregs but it cannot be tolerated by all patients due to significant toxicities including capillary leak syndrome (CLS), hypotension, and renal failure. Certepeptide, a tumor-targeting CendR-peptide, is in phase 2 trials for metastatic PC to enhance chemotherapy delivery by binding tumor-specific integrins and NRP-1. We hypothesized that certepeptide could direct LD IL-2 into PC, concentrating it within tumors, to activate CD8+ T-cells, reduce tumor growth, and increase survival while minimizing systemic toxicity.
Methods
Orthotopic KPC pancreatic tumors were induced in mice, treated with combinations of certepeptide (150 μg/mouse) and IL-2 (0.25 mg/kg LD or 25 mg/kg HD) 3/week. Tumor weight, survival, and CD8+ T-cell activity (proliferation, activation, cytotoxicity) were analyzed. CD8+ T-cell depletion and lung tissue analyses assessed IL-2-induced CLS.
Results
Certepeptide + LD IL-2 significantly reduced tumor weight and increased survival (median 2.7 vs. 0.7 months, p<0.0001) compared to monotherapies, without cachexia or CLS. This combination enhanced cytotoxic T-cell activity, demonstrated by increased p-STAT5, Granzyme B, and cl-Caspase 3, without increasing Treg numbers. CD8+ T-cell depletion abrogated these effects, confirming their critical role.
Conclusions
Certepeptide + LD IL-2 is a novel, effective approach for PC, enhancing CD8+ T cell cytotoxicity within the TIME without increasing Tregs or severe IL-2 related toxicities. This therapy significantly prolongs survival in preclinical models, warranting phase 2 trials in pancreatic cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
UCSD Moores Cancer Center.
Funding
NIH (Cancer Centers Support Grant), NCI.
Disclosure
All authors have declared no conflicts of interest.