74 Chapter 4 Limitations and Challenges of Programmed Cell Death-1/Programmed Cell Death Ligand-1 Imaging Currently, multiple clinical PD-1/L1 imaging studies are awaited or ongoing (Table 2). Their main hypothesis is that PD-1/PD-L1 imaging will enable us to (1) study the tumor and normal tissue targeting of PD-1/L1 ICI, (2) determine the correlation between PD-1/PD-L1 targeting of various metastases and their response to ICI, (3) understand the mechanism of action of ICI, and (4) assess the dynamics of PD-L1/PD-1 on anticancer treatment. First clinical studies have demonstrated that PD-1/PD-L1 imaging using radiolabeled antibodies, small peptides or sdAbs is feasible and safe. Their results suggest a relation between tracer uptake and IHC PD-L1 expression, as well as a relation between tracer uptake and ICI response. However, they were conducted in a limited number of patients and besides technical limitations, the correct interpretation of tracer uptake is challenging, and various contributing factors should be taken into account. For example, the image quality of PET imaging is limited by the low spatial resolution that results in a partial volume effect mainly affecting small and low-contrast tumor lesions. Also, measurement errors can occur due to a low signal-to-noise ratio, caused by low injected activity doses and the low positron abundance of 89Zr 55. Therefore, heterogenic tracer uptake should be interpreted with caution in the absence of histologic confirmation of target expression, as visual variable uptake may not reflect true heterogenic PD-L1 expression, but noise-induced variability of the quantitative target uptake measurements as previously described by Jauw and colleagues55. Variable tracer uptake may also result from differences in perfusion and accessibility in tumor and normal tissues56. Thus, it could be that PD-1/PD-L1 expression is present, but due to limited perfusion, the radiolabeled antibody is not able to reach its target. Third, knowledge on the target expression levels is not only essential to accurately interpret the acquired scan, but also to find optimal dosing levels for imaging. Immune cells in the spleen often express PD-L1 because of their physiologic role in regulating the immune response. Therefore, the spleen acts as a sink organ for PD-L1 radiotracers. At low antibody doses, most of the injected tracer will accumulate in the spleen, resulting in rapid blood clearance and minimal targeting to other PD-L1–positive tissues like the tumor44,57. By increasing the antibody dose, spleen uptake saturates, resulting in restored circulation time and increased targeting to tumor and other PD-L1– positive tissue52. Contrary to PD-L1, expression levels of PD-1 on immune cells are much lower and there is no sink organ affecting the biodistribution of PD-1 targeting tracers. Therefore, lower doses should be used to prevent saturation of all PD-1 and to obtain high-contrast images43,53. The physiologic presence of PD-1/PD-L1 in various types of cells (e.g., tumor, immune, or other cell types), challenges the interpretation of visual tracer uptake43,44,57. Histologic confirmation is therefore advisable and, for example, multiplex IHC could be used for the identification of each cell type, taken all previously mentioned limitations of IHC on tumor biopsies into account. The addition of another imaging technique (e.g., PET with fludeoxyglucose F 18) is also worth considering distinguishing between physiologic targeting from receptor-mediated targeting or identify different cell types. However, this remains extremely challenging.
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