Objective:

To characterize the target landscape of PD1-IL2v in matched PBMCs and TILs from treatment-naïve patients, focusing on receptor density and subset prevalence.

Key Findings:

• TILs are enriched with stem-like CD8+ T cells and Tregs, with PD-1 receptor density increased up to three-fold on CD8+ TILs compared to PBMCs, suggesting enhanced targeting potential.
• PD1-IL2v preferentially targets CD8+ TIL subsets over Tregs, resulting in superior biological activity, which may improve therapeutic outcomes.
• Higher STAT5 phosphorylation was observed in stem-like and effector CD8+ T cells compared to Tregs, confirming effective targeting and potential for enhanced anti-tumor response.

Interpretation:

The study provides translational validation for PD1-IL2v’s mechanism, highlighting PD-1 receptor density and subset prevalence as critical factors for drug activity, which could inform future therapeutic strategies.

Limitations:

• The study is ex-vivo and may not fully replicate in vivo conditions, potentially limiting the applicability of findings.
• Limited to matched PBMCs and TILs from treatment-naïve patients across seven cancer types, which may restrict generalizability.

Conclusion:

The findings support PD1-IL2v's potential for selective intra-tumoral immune stimulation while minimizing Treg activation, suggesting a promising avenue for enhancing cancer immunotherapy.