Abstract B090: Defining The Immune Mechanisms Required For iRGD-guided Low Dose IL-2 Therapy in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PCAD) remains one of the deadliest cancers with minimal treatment options, highlighting the need for more effective immunotherapeutic strategies capable of overcoming its highly immunosuppressive tumor microenvironment. Tumor penetrating peptides such as iRGD enhance the delivery and distribution of therapies within tumors, offering a promising approach to improve treatment efficacy. Initially, we found that combining non-toxic doses of interleukin-2 (IL-2) with iRGD effectively controls PDAC tumors in mice. This study investigates the contributions of natural killer (NK) cells and CD8 T-cells to iRGD + IL-2 mediated tumor control by comparing their abundance and activation across treatment groups. While high dose (HD) IL-2 increased the number of cytotoxic immune cells, these cells exhibited reduced toxicity and increased signs of exhaustion. In contrast, our findings suggest that quality of the immune response, reflected by immune cell activation rather than abundance, is associated with tumor control following combination therapy. No significant difference in NK cell numbers were observed among the control, iRGD, Low dose (LD) IL-2, HD IL-2, and iRGD + LD IL-2 groups, although NK cell numbers showed an increasing trend in the HD IL-2 and iRGD + LD IL-2 groups. CD8 T-cell activation was significantly increased in the iRGD + LD IL-2 combination group. Studies evaluating NK cell activation are ongoing. These findings suggest that the enhanced antitumor activity of iRGD + LD IL-2 may be associated with increased CD8 T-cell activation rather than expansion of cytotoxic immune cell populations. These results support the development of iRGD-based combination immunotherapies as a strategy to enhance antitumor immunity while minimizing the toxicities associated with HD IL-2, with potential translational applications for patients with PDAC.