Interleukin-2 PET imaging in patients with metastatic melanoma before and during immune checkpoint inhibitor therapy

Pim P van de Donk, Thijs T Wind, Jahlisa S Hooiveld-Noeken, Elly L van der Veen, Andor W J M Glaudemans, Arjan Diepstra, Mathilde Jalving, Elisabeth G E de Vries, Erik F J de Vries, Geke A P Hospers, Pim P van de Donk, Thijs T Wind, Jahlisa S Hooiveld-Noeken, Elly L van der Veen, Andor W J M Glaudemans, Arjan Diepstra, Mathilde Jalving, Elisabeth G E de Vries, Erik F J de Vries, Geke A P Hospers

Abstract

Purpose: Immune checkpoint inhibitors can induce a T cell-mediated anti-tumor immune response in patients with melanoma. Visualizing T cell activity using positron emission tomography (PET) might allow early insight into treatment efficacy. Activated tumor-infiltrating T cells express the high-affinity interleukin-2 receptor (IL-2R). Therefore, we performed a pilot study, using fluorine-18-labeled IL-2 ([18F]FB-IL2 PET), to evaluate whether a treatment-induced immune response can be detected.

Methods: Patients with metastatic melanoma received ~ 200 MBq [18F]FB-IL2 intravenously, followed by a PET/CT scan before and during immune checkpoint inhibitor therapy. [18F]FB-IL2 uptake was measured as standardized uptake value in healthy tissues (SUVmean) and tumor lesions (SUVmax). Response to therapy was assessed using RECIST v1.1. Archival tumor tissues were used for immunohistochemical analyses of T cell infiltration.

Results: Baseline [18F]FB-IL2 PET scans were performed in 13 patients. SUVmean at baseline was highest in the kidneys (14.2, IQR: 11.6-18.0) and liver (10.6, IQR: 8.6-13.4). In lymphoid tissues, uptake was highest in spleen (10.9, IQR: 8.8-12.4) and bone marrow (2.5, IQR: 2.1-3.0). SUVmax in tumor lesions (n = 41) at baseline was 1.9 (IQR: 1.7-2.3). In 11 patients, serial imaging was performed, three at week 6, seven at week 2, and one at week 4. Median [18F]FB-IL2 tumor uptake decreased from 1.8 (IQR: 1.7-2.1) at baseline to 1.7 (IQR: 1.4-2.1) during treatment (p = 0.043). Changes in [18F]FB-IL2 tumor uptake did not correlate with response. IL-2R expression in four archival tumor tissues was low and did not correlate with baseline [18F]FB-IL2 uptake. No [18F]FB-IL2-related side effects occurred.

Conclusion: PET imaging of the IL-2R, using [18F]FB-IL2, is safe and feasible. In this small patient group, serial [18F]FB-IL2-PET imaging did not detect a treatment-related immune response.

Trial registration: Clinicaltrials.gov : NCT02922283; EudraCT: 2014-003387.20.

Keywords: Immunotherapy; Interleukin-2; Melanoma; Positron emission tomography; T cells.

Conflict of interest statement

MJ: advisory board, honoraria to institution: Merck, BMS, Novartis, Pierre Fabre, Tesaro, AstraZeneca. Clinical studies: BMS, AbbVie, Merck, Cristal Therapeutics. GH: consulting and advisory role: Amgen, Roche, MSD, BMS, Pfizer, Novartis, Pierre Fabry, paid to the institution (UMCG). Research grant BMS, Seerave, paid to the institution (UMCG). EdV: Institutional financial support for consulting and advisory role for Sanofi, Daiichi Sankyo, NSABP, Pfizer, Merck, and institutional financial support for clinical trials or contracted research from Amgen, Genentech, Roche, AstraZeneca, Synthon, Regeneron, Bayer, Chugai Pharma, CytomX Therapeutics, Servier, Nordic Nanovector, G1 Therapeutics, Radius Health; all outside the submitted work. No other potential conflicts of interest relevant to this article exist.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Biodistribution of [18F]FB-IL2. A Median tracer uptake of healthy tissues, expressed as SUVmean with interquartile range on the baseline [18F]FB-IL2-PET scans (n = 13) and on-treatment [18F]FB-IL2-PET scans (n = 11). B Example of a maximum intensity projection of the [18F]FB-IL2-PET scan
Fig. 2
Fig. 2
Example of high tracer uptake in the lungs. A Transversal PET/CT image of three regions showing high [18F]FB-IL2 uptake. B Maximum intensity projection of the same patient showing multiple areas of high tracer accumulation in the lungs
Fig. 3
Fig. 3
Uptake of [18F]FB-IL2 in tumor lesions. A Tracer uptake (SUVmax) in individual tumor lesions per imaging timepoint, horizontal bars represent median with interquartile range. B Example of transversal PET/CT image of an adrenal gland metastasis showing [18F]FB-IL2 uptake (SUVmax of 5.2)
Fig. 4
Fig. 4
Analyses of [18F]FB-IL2 in plasma. A Plasma activity over time, expressed as standardized uptake value (mean ± standard deviation). B Tracer integrity over time, expressed as the percentage of intact tracer (mean ± standard deviation).*P < 0.05
Fig. 5
Fig. 5
Immunohistochemistry for T cell markers on archival tumor tissue samples. IHC scores are expressed as mean counts/mm2 with standard deviation. Abbreviation used: IHC, immunohistochemistry

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