Eciskafusp alfa (PD1-IL2v) selectively targets CD8+ TILs over Tregs in solid tumors by leveraging increased PD-1 density

Despite the promise of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis in oncology, a significant subset of patients do not respond or develop resistance, highlighting the need for more efficacious therapies. Traditional IL-2 therapies can activate immunosuppressive regulatory T cells (Tregs), limiting their anti-tumor efficacy and contributing to systemic toxicity. Eciskafusp alfa (PD1-IL2v) is a novel immunocytokine engineered for avidity-driven, cis-delivery of IL-2R agonism specifically to PD-1+ cells, aiming to enhance anti-tumor immunity while minimizing Treg activation.

This study conducted a comprehensive ex-vivo characterization of Eciskafusp alfa's (PD1-IL2v) target landscape. Researchers utilized matched peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) obtained from patients across seven solid tumor indications. They assessed PD-1 receptor density on various T cell subsets and evaluated the preferential targeting and biological activity of PD1-IL2v by measuring STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8+ T cells versus Tregs.

The tumor-infiltrating lymphocyte (TIL) compartment was significantly enriched with both stem-like CD8+ T cells and immunosuppressive regulatory T cells (Tregs). Notably, PD-1 receptor density was increased up to three-fold on CD8+ TILs compared to PBMCs, providing a clear basis for preferential intra-tumoral targeting. Ex-vivo assays demonstrated that PD1-IL2v preferentially targets CD8+ TIL subsets (both stem-like and effector) over Tregs. This selective targeting translated into superior biological activity:

PD1-IL2v induced higher STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8+ T cells compared to Tregs, confirming its intended cis-targeting and enhanced IL-2R agonism. These findings provide translational validation for PD1-IL2v's mechanism, demonstrating selective intra-tumoral immune stimulation while minimizing Treg activation across multiple solid tumor types.