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

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.

Shining Damaged Hearts: Immunotherapy-Related Cardiotoxicity in the Spotlight of Nuclear Cardiology

“…The inhibition of these receptors led to the development of multiple immunotherapy bioengineered agents, some of which block PD-1 and CTLA-4 on T cells and others of which block the PD-1 ligand PD-L1 on tumor cells leading the immune system to recognize cancer cells and destroy them. Whole-body PD-1 and PD-L1 PET (imaging the targets of immune checkpoint inhibitor therapy) can be performed using various radionuclides including 18 F-BMS-98619210 (targeting PD-L1), 89 Zr-pembrolizumab, 89 Zr-atezolizumab, 89 Zr-nivolumab [ 158 , 159 , 160 , 161 ], or 64 Cu-labeled PD-1 and PD-L1 antibodies [ 162 ].…”

Preclinical antibody-PET imaging of PD-L1

“…As the two are so heavily related, monitoring the expression of both PD1 and its ligand PD-L1 may prove useful in a clinical setting. We therefore direct the reader to the other reviews for further information on PD1 imaging (2,14).…”

“…Cancer cells upregulate cell-surface PD-L1 levels to increase PD-1-mediated inhibitory signaling, and antibodies that target PD-L1 have shown impressive clinical outcomes for multiple cancers (1). At the time of this review, there are three clinically-approved antibodies specific for PD-L1: Atezolizumab, Avelumab, and Durvalumab (2,3). In addition to being used as therapeutics, anti-PD-L1 antibodies labeled with positron emitters can be employed as companion diagnostics and allow assessment of PD-L1 protein levels and therapeutic response in patients with cancer (4).…”

“…Indeed, the extensive heterogeneity of PD-L1 expression across the entire tumor volume results in inaccurate patient stratification when using minimal tissue biopsies for IHC (5)(6)(7). Immuno-PET has demonstrated great promise in determining protein levels and heterogeneity of immune checkpoint PD-L1 (2), which allows patient stratification, prediction and monitoring response to immune checkpoint inhibitors non-invasively across a patient's therapy regime.…”

“…In 2018, two landmark publications showed the feasibility and safety of radiolabelled agents targeted toward PD-L1 (8,9) to non-invasively image its expression in human tumors and healthy tissues. For information on considerations for the development and use of PD-L1 tracers in the clinic and early preliminary work conducted prior to 2018, we refer the reader to other reviews (2,3). Here, we concisely review preclinical PD-L1 PET imaging research, which has followed the landmark publications of 2018.…”