69 PD-1/PD-L1 PET imaging: A novel tool to optimize immunotherapy? INTRODUCTION Programmed Cell Death-1/Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitors Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (ligand)-1 (PD-[L]1) axis have emerged at the forefront of cancer treatment.1 Numerous ICIs have received Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval as first-line or second-line treatment in patients with relapsed or metastatic malignancies, including non–small cell lung cancer (NSCLC)2-4, melanoma5,6, head and neck cancer4,7, Merkel cell carcinoma8, renal cell carcinoma9, and urothelial cell cancer10-12. Currently, indications are rapidly expanding, including in the neo-adjuvant setting13. Two key factors that determine success of ICI are the presence of PD-L1 and infiltration of distinct immune cell populations in the tumor microenvironment14-18. Their dynamic and mobile nature highlights the complexity of ICI response. So far, favorable responses have been associated with high tumor PD-L1 expression and high T-cell infiltration. Despite promising clinical results, still only a subset of patients shows durable responses to ICI targeting PD-1/PD-L1 and objective response rates are limited to 20% to 40% of patients1. The immune histochemical analysis (IHC) of tumor PD-L1 expression currently is the only registered biomarker for treatment selection13-15. It must be noted that patients with tumors stained negative for PD-L1 on a tumor biopsy can benefit from ICI2,3. Thus, there is a need for a robust marker for ICI response19. In this review, we focus on the prospect of clinical PD-1/PD-L1 imaging studies using radiolabeled antibodies as a tool to predict ICI response and improve our understanding of the tumor microenvironment to optimize the use of ICI20. Programmed Cell Death Ligand-1 Expression as a Marker for Immune Checkpoint Inhibitor Response The association between high PD-L1 expression in the tumor and ICI response has resulted in the recommendation of the FDA/EMA to restrict the use of pembrolizumab (e.g., as first-line treatment for advanced or metastasized NSCLC) to patients with a PD-L1 expressing tumors as assessed by IHC2. However, the IHC assessment of PD-L1 on tumor biopsies has several limitations that comprise its clinical use. First, PD-L1 assessment using IHC on biopsies or single tissue specimen is limited by the heterogeneous tissue expression of PD-L121. This has been illustrated by heterogenic PD-L1 expression between primary tumors and metastases within one patient22,23. Intra-tumoral heterogeneity, the discordant PD-L1 expression between tumor biopsy and surgical specimen from one tumor, adds the risk of sampling error and could lead to an overestimation or underestimation of the PD-L1 status of all tumor tissue in a patient24. Furthermore, PD-L1 expression varies over time, in response to a constantly evolving immune response1 and to anticancer treatment as demonstrated by the upregulation of PD-L1 after radiotherapy treatment25. 4
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