Chapter 2 50 Discussion Monoclonal antibodies that block the PD-1–PD-L1 axis have transformed the therapeutic arsenal of advanced stage NSCLC. Nevertheless, most patients still do not benefit from PD-1 blockade, while they are exposed to the risk of treatment-related toxicity. Because of this, there is an evident clinical need for predictive biomarkers that can help reduce overtreatment. Based on the rationale that the presence of tumor-reactive PD-1T T lymphocytes is indicative of an ongoing anti-tumor response10, we here assess the predictive value of PD-1T TILs using an algorithmbased quantitative PD-1 IHC assay in FFPE tissue sections. We establish PD-1T TILs as predictive marker in two independent advanced stage NSCLC cohorts treated with PD-1 blockade. Our data show that particularly low numbers of PD-1T TILs accurately identify a patient group with no clinical benefit. Furthermore, high PD1T TIL infiltration was observed in >90% of patients with DC 12m. The high sensitivity and NPV of our biomarker of more than 90% with a specificity of more than 50% should thus allow to reduce overtreatment while minimizing undertreatment. Interobserver variability in the assessment of biomarkers often affects their predictive value. Here, we report a reliable and automated method to perform digital quantification of PD-1T TILs, based on an approach established in our earlier work10. Previous studies have shown the advantage of digital quantification by improving accuracy and standardization of biomarkers37–39. While our method allows automated quantification of PD-1T TILs, it still requires a substantial user interaction, for instance as tumor areas need to be manually annotated. Hence, for implementation into clinical practice further studies are required to assess methods that could improve standardization across centers, for instance using artificial intelligence (AI) solutions. Another common hurdle for biomarker development is caused by tumor heterogeneity. Therefore, we aimed to understand whether heterogeneity in PD-1T TILs occurs within and across lesions and whether the presence of PD-1T TILs may thus be predictive for the capacity of locally residing T cells to mediate anti-tumor immunity upon PD-1 blockade. To this end, we first assessed responses at lesionlevel in patients defined as clinical progressors by RECIST criteria. Importantly, we observed that only a minority of the assessed lesions in the PD-1T high group progressed as compared to the PD-1T low group, indicating a good correlation between the biomarker and lesion-specific response. To assess the impact of intratumoral heterogeneity, we quantified PD-1T TILs in multiple randomly selected small tumor areas. Despite some level of variation, the vast majority of individual measurements
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