70 Chapter 4 Second, each available validated IHC-assay uses different antibody clones, platforms, thresholds, and scoring algorithms26-28. The feasibility of harmonizing the clinical use of 4 commercial PD-L1 IHC assays has been studied in NSCLC, concluding that 3 of 4 assays are able to similarly detect tumor PD-L1 expression29,30. Nevertheless, interchanging assays and cutoffs leads to “misclassification” of PD-L1 status for 37% of patients, and this has important clinical consequences, as patients are potentially withheld from ICI treatment29,30. The pitfalls in the IHC analysis of PD-L1 have boosted the development of new tumor tissue, blood-based, and imaging biomarker research strategies (Table 1). Examples are multiplex IHC that allows for simultaneous quantification of multiple immune checkpoint molecules differentially expressed on immune and tumor cells31,32. Furthermore, the assessment of PD-L1 using nextgeneration sequencing (NGS) has shown comparable results to PD-L1 IHC analyses33 and bloodbased biomarkers such as PD-11 CD8+ T cells have been associated with response to PD-1 targeting ICI34,35. Also, PD-L1 expressing circulating tumor cells showed a good correlation with tumor PD-L1 and might serve as a predictor of early response to ICI targeting PD-136,37. Table 1. Summary of the characteristics of the currently explored biomarkers to visualize PD-1/PD-L1 Ideal PD-1/PD-L1 biomarker features IHC Flow cytometry* NGS** PD-1/PD-L1 PET Non-invasive - √√ - √√ Cheap √√ √ - - Fast √ √ √ - Longitudinal / dynamic - √√ - √√ Whole-body - - - √√ Applicable in clinic / as standard √√ √√ √ √ Quantification √ √ √ √ Sensitivity √ √ √ √√ √√: yes, √: moderate, -: no, * Blood based, ** Tumor tissue based Molecular imaging modalities can function as a complementary tool to guide the development of effective ICI treatment strategies38. Using radiolabeled tracers, molecular imaging allows noninvasive visualization of all accessible PD-1/PD-L139-43, including its heterogeneous expression across metastases on a whole-body level. This approach also suits the dynamic nature of PD-L1/ PD-1, as it reflects the actual PD-L1/PD-1 status instead of a historical PD-L1/PD-1 status that may have been subject to change. Repetitive imaging enables on-treatment assessment of PD-L1 expression and provides a unique insight into the therapy-induced changes44 and might support alternative treatment planning (e.g., radiotherapy before ICI in low PD-L1 expression tumor lesions). Finally, it allows for a better understanding of the in vivo distribution and behavior of targeted drugs; for example, drug delivery over time, drug dynamics related to dosing39,45.
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