Frontiers in immunology · 2026
Target receptor expression dictates the selective intra-tumoral targeting of CD8+ T cells by eciskafusp alfa in matched PBMCs and TILs from CPI-naïve patients.
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Manchala Amrita, Varypataki Eleni Maria, Charo Jehad, Umaña Pablo, Klein Christian, Codarri Deak Laura
Аннотация
INTRODUCTION: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have shown considerable promise as a therapeutic modality in oncology. Despite their ability to target stem-like CD8+ T cells and give rise to exhaustion-fated effector CD8+ T cells, a significant subset of patients do not respond or eventually develop resistance, highlighting the need for more efficacious therapies. Eciskafusp alfa (PD1-IL2v) is a novel immunocytokine, engineered for avidity-driven, cis-delivery of IL-2R agonism to PD-1+ cells.
METHODS: This study provides a comprehensive ex-vivo characterization of PD1-IL2v's target landscape using matched peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) from patients across seven solid tumor indications.
RESULTS: We confirmed that the TIL compartment is 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, establishing the basis for preferential intra-tumoral targeting. Ex-vivo assays demonstrated that PD1-IL2v preferentially targets CD8+ TIL subsets (stem-like and effector) over Tregs. This preferential targeting translated into superior biological activity, with PD1-IL2v inducing higher STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8+ T cells compared to Tregs, confirming the intended cis-targeting and enhanced IL-2R agonism.
DISCUSSION: These findings provide translational validation for PD1-IL2v's mechanism, demonstrating selective intra-tumoral immune stimulation while minimizing Treg activation. This characterization identifies PD-1 receptor density and subset prevalence as critical factors for drug activity and represents potentially useful biomarkers for predicting patient responsiveness and guiding patient selection.
METHODS: This study provides a comprehensive ex-vivo characterization of PD1-IL2v's target landscape using matched peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) from patients across seven solid tumor indications.
RESULTS: We confirmed that the TIL compartment is 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, establishing the basis for preferential intra-tumoral targeting. Ex-vivo assays demonstrated that PD1-IL2v preferentially targets CD8+ TIL subsets (stem-like and effector) over Tregs. This preferential targeting translated into superior biological activity, with PD1-IL2v inducing higher STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8+ T cells compared to Tregs, confirming the intended cis-targeting and enhanced IL-2R agonism.
DISCUSSION: These findings provide translational validation for PD1-IL2v's mechanism, demonstrating selective intra-tumoral immune stimulation while minimizing Treg activation. This characterization identifies PD-1 receptor density and subset prevalence as critical factors for drug activity and represents potentially useful biomarkers for predicting patient responsiveness and guiding patient selection.