[99mTc]-labelled anti-Programmed Death-Ligand 1 single-domain antibody SPECT/CT: a novel imaging biomarker for myocardial PD-L1 expression

Abstract

Background: Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using [^99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT.

Methods: Thoracic [^99mTc]NM-01 SPECT/CT was performed in lung cancer patients (n = 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LV_max:BP) and (RV_max:BP) were measured. LV_max was compared to background skeletal muscle (muscle_max). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland-Altman analysis.

Results: Mean LV_max:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks (p = 0.42). Mean RV_max:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks (p = 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LV_max to muscle_max 3.71 ± 0.77 vs 0.98 ± 0.20 (p < 0.001)) and at least twofold for the RV (LV_max to muscle_max 2.49 ± 0.63 vs 0.98 ± 0.20 (p < 0.001)). There was excellent intra-rater reliability for LV_max:BP with ICC 0.99 (95% confidence interval 0.94-0.99, p < 0.001), mean bias -0.05 ± 0.14 (95% limits of agreement -0.32 to 0.21). There were no major adverse cardiovascular events or myocarditis during follow-up.

Conclusion: This study is the first to report PD-L1 expression of the heart that can be quantified non-invasively without invasive myocardial biopsy, with high reliability and specificity. This technique can be applied to investigate myocardial PD-L1 expression in ICI-associated myocarditis and cardiomyopathies. Clinical trial registration PD-L1 Expression in Cancer (PECan) study (NCT04436406). https://clinicaltrials.gov/ct2/show/NCT04436406 June 18th, 2020.

Keywords: Immune checkpoint inhibitor; PD-L1 expression; SPECT-CT.

Fig. 1

Sample image of region of interest of the myocardium for quantitative assessment of myocardial PD-L1 expression

Fig. 2

Baseline [^99mTc]NM-01 SPECT/CT images for a patient with non-small cell lung cancer. In addition to the uptake of [^99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) in the right lung tumour, tracer uptake is seen in the myocardium. The left ventricular: blood pool maximum region of interest (ROI_max) ratio was 3.1, and the right ventricular: blood pool ratio was 1.5. In addition, there is a normal distribution of hepatic, bone marrow, splenic and renal activity. Very low muscle activity is present in the paraspinal muscles, in contrast to the increased myocardial PD-L1 expression

Fig. 3

Bland-and-Altman plots that demonstrate intra-rater reliability for ROI_max ratios for [^99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT (A) left ventricular: blood pool and (B) right ventricular: blood pool. (Blue dotted line: mean bias, red dotted lines: 95% limits of agreement)