132 Chapter 7 DISCUSSION To increase our current understanding of response and (primary) resistance to ICI treatment, 89Zr-labeled ICI PET imaging can make an important contribution to the field. It enables the in-vivo visualization of the biodistribution of ICI which allows to address questions on the relation between antibody dose and tumor uptake, the relevance of heterogeneous antibody accumulation across different regions within the tumor, and the role of Fc-tail modification or antibody isotypes12. Furthermore, antibody-based PET imaging may visualize different inhibitory and stimulatory immune checkpoints on tumors, immune cells, and healthy tissue. These tools allow to study changes in intra-tumoral accumulation in combination treatments with other therapeutic antibodies or local/systemic treatments that may influence accumulation in the tumor, such as radiotherapy or anti-angiogenesis treatment13. Comparison of data at immune cell subset and lesion level remains difficult and is hard to interpret. As discussed by Niemeijer and colleagues9, PD-1 is expressed by several immune cells, including exhausted effector cells, and antigen-presenting cells, such as dendritic cell subsets. Non-malignant lymph nodes also showed [89Zr]Zr-pembrolizumab uptake, which was demonstrated in one patient with the impression of a non-malignant axillary lymph node on [18F]FDG PET/CT scan and biopsyproven PD-1 positive lymphocytes. The authors do not specify whether the PD-1 expression was seen on antigen-presenting cells or T cell subsets. The difficulty in PET radiolabeled PD-1 imaging is also that lesions are more difficult to delineate in patients treated with a pre-dose of the ICI therapy. This can be explained by low numbers of PD-1 positive cells in the tumor, migration of PD-1 positive T cells, and by PD-1 receptor occupation and saturation upon treatment, causing a loss of signal in 89Zr-labeled anti-PD-1 imaging. PET with radiolabeled ICIs may therefore contribute to an improved understanding of the on-treatment antibody behavior in blood, tumor, and normal tissue, such as secondary lymphoid tissues. If baseline or early identification of responding patients is conceivable, this is of great importance to prevent unnecessary immune-related adverse events and costs14. Data interpretation is different when a PD-L1 checkpoint inhibitor is used. PD-L1 is for example highly expressed by splenic cells. Due to the sink organ capacity of the spleen, there is a dosedependent targeting of other PD-L1 positive cells, in particular cancer cells15. Also, translating the quantification of [89Zr]Zr-atezolizumab uptake to PD-L1 expression is difficult, since the presence of the tracer may be the result of favorable vascularization and/or permeability rather than target expression. This can still be beneficial for the response to ICI treatment, but traceruptake should be interpreted cautiously. The intra- and interlesional heterogeneity in tumor tracer-uptake was described in all three 89Zr-labeled ICI PET imaging studies9-11. Niemeijer et al.9 reported that not even half of the lesions with a diameter ≥2 cm showed uptake on [89Zr]Zr-pembrolizumab PET/CT scan. In the [89Zr]Zr-atezolizumab imaging trial uptake of [89Zr]Zr-atezolizumab strongly correlated with clinical response, while [89Zr]Zr -nivolumab uptake only correlated with lesional response10,11. These above-mentioned phenomena may have significant
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