Noninvasive Monitoring of Programmed Death-Ligand 2 Expression with Positron Emission Tomography using ⁶⁸Ga-labeled Peptide Antagonist in Preclinical and Exploratory Human Studies

While the expression of programmed death ligand-1 (PD-L1) is associated with response to immune therapy, PD-L1-negative patients may still benefit from immune treatment. Programmed death ligand-2 (PD-L2), another crucial immune checkpoint molecule interacting with PD-1, correlates with the efficacy of various tumor immune therapies. This study investigates the expression of PD-L2 in non-small cell lung cancer (NSCLC) patients following anti-PD-1 therapy and its predictive value for clinical survival outcomes. Additionally, we explore the noninvasive, real-time, and dynamic quantitative analysis potential of PD-L2 positron emission tomography (PET) imaging in transplanted tumors. We utilized [⁶⁸Ga]Ga-labeled peptide HN11-1 for PD-L2 PET imaging. The results indicate a higher response rate to anti-PD-1 therapy in patients positive for both PD-L1 and PD-L2, with PD-L2 status independently predicting progression-free survival (PFS) with pembrolizumab treatment. Furthermore, [⁶⁸Ga]Ga-HN11-1 PET imaging demonstrates specificity in assessing PD-L2 status. Overall, we confirm the correlation between high PD-L2 expression and favorable PFS in NSCLC patients post anti-PD-1 therapy and highlight the promising potential of [⁶⁸Ga]Ga-HN11-1 as a specific tracer for PD-L2 in preclinical and initial human trials.