Pharmacokinetic analysis and simplified uptake measures for tumour lesion [18F]F-AraG PET imaging in patients with non-small cell lung cancer

Abstract

Introduction: The novel positron emission tomography (PET) imaging tracer, [¹⁸F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [¹⁸F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.

Methods: Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.

Results: Whole-blood and plasma radioactivity concentrations showed rapid clearance of [¹⁸F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [¹⁸F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived K_i. The correlation of TBR at 60-70 min p.i. with 2T3K-derived K_i (r (df = 20) = 0.87, p < 0.01), was stronger than for SUV_BW (r (df = 20) = 0.80, p < 0.01).

Conclusion: Tumour lesion [¹⁸F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [¹⁸F]F-AraG uptake in patients with NSCLC.

Keywords: Activated T-cells; ImmunoPET; Pharmacokinetic modelling; [18F]F-AraG.

Fig. 1

Maximum intensity projection of a 60–70 min p.i. [¹⁸F]F-AraG PET scan of a 63 yrs old male patient with advanced stage NSCLC. Physiological uptake can be observed in the liver, kidneys, spleen, bladder, myocardium, bone marrow and thyroid, pituitary and salivary glands. Additionally, high uptake can be seen in tumour lesions (lung) and bone metastases (right jaw, both humeri, sternum, multiple vertebrae and right acetabulum)

Fig. 2

Blood sampling time activity curves. Mean [¹⁸F]F-AraG activity concentration in whole-blood (a) and plasma (b) expressed in SUV_BW, plasma/whole-blood ratios (c) and [¹⁸F]F-AraG parent fractions (d) over time. Data of thirteen patients are shown, except for (d) where data was missing for patients ATT03 and ATT04. The error bars represent one SD from the mean. Individual patient data is represented by grey lines

Fig. 3

Mean organ and tumour [¹⁸F]F-AraG uptake over time expressed in SUV_BW derived from N scans. The error bars represent one standard deviation from the mean

Fig. 4

[¹⁸F]F-AraG uptake in tumour lesions over time expressed in SUV_BW

Fig. 5

Correlation between simplified uptake measures and 2T3k-derived K_i. Scatter plots showing tumour lesion [¹⁸F]F-AraG uptake (a) expressed in SUV_BW at 60–70 min p.i. against 2T3k-derived K_i, and (b) expressed in TBR at 60–70 min p.i. against 2T3k-derived K_i. Note that multiple data points from the same lesion are represented in the figure, but only one data point per lesion was used for correlation analyses. Multiple tumour lesions were quantified for the SHARP patients and are presented in the same colour. For patient ATT07, the presented SUV_BW and TBR were obtained at 50–60 min p.i