Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic.

David Leung,Ralph Adam Smith,Wendy Hayes,Wolfgang Weber,Samuel Bonacorsi

doi:10.3389/fonc.2021.698425

Abstract

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.

Highlights

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) checkpoint inhibition plays a critical part in improving prognoses for patients with a range of tumor types [1]
There are limited data available showing association of PD-L1 expression assessed by molecular imaging with efficacy, encouraging results were provided by the first-in-human study of 89Zr-atezolizumab, in which clinical response was better correlated with pretreatment positron emission tomography (PET)-imaging–assessed PD-L1 expression compared with either IHC-based or RNAsequencing–based PD-L1 assays [73]
There are opportunities and challenges facing the incorporation of molecular imaging for PD-(L)1 expression into drug development and routine clinical practice

Summary

INTRODUCTION

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) checkpoint inhibition plays a critical part in improving prognoses for patients with a range of tumor types [1]. There are limited data available showing association of PD-L1 expression assessed by molecular imaging with efficacy, encouraging results were provided by the first-in-human study of 89Zr-atezolizumab, in which clinical response was better correlated with pretreatment PET-imaging–assessed PD-L1 expression compared with either IHC-based or RNAsequencing–based PD-L1 assays [73]. These findings demonstrate that tumors that use PD-L1 for immune escape can be readily targeted by nivolumab immune blockade [72] This suggests that PD-L1 determination by molecular imaging or other methods may facilitate the selection of patients who are most likely to respond to treatment with ICIs. Affirming the Use of PD-L1 PET Tracers in Clinical Studies: Assessment of PD-L1 Expression by IHC and Molecular Imaging. Agreement between PD-L1 IHC and molecular imaging has been assessed in a number of TABLE 1 | Examples of clinically tested PD-(L) PET tracers

Key findings

Findings

DISCUSSION