Early Phase I Study of a 99mTc-Labeled Anti-Programmed Death Ligand-1 (PD-L1) Single-Domain Antibody in SPECT/CT Assessment of PD-L1 Expression in Non-Small Cell Lung Cancer

Yan Xing, Gitasha Chand, Changchun Liu, Gary J R Cook, Jim O'Doherty, Lingzhou Zhao, Nicholas C L Wong, Levente K Meszaros, Hong Hoi Ting, Jinhua Zhao, Yan Xing, Gitasha Chand, Changchun Liu, Gary J R Cook, Jim O'Doherty, Lingzhou Zhao, Nicholas C L Wong, Levente K Meszaros, Hong Hoi Ting, Jinhua Zhao

Abstract

Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer. Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site-specifically with 99mTc for SPECT imaging, we aimed to assess the safety, radiation dosimetry, and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results. Methods: Sixteen patients (mean age, 61.7 y; 11 men) with non-small cell lung cancer were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [99mTc(OH2)3(CO)3]+ complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8-10.4 MBq/kg, corresponding to 100 μg or 400 μg of NM-01. Whole-body planar and thoracic SPECT/CT scans were obtained at 1 and 2 h after injection in all patients, and 5 patients underwent additional imaging at 10 min, 3 h, and 24 h for radiation dosimetry calculations. All patients were monitored for adverse events. Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84 × 10-3 ± 9.33 × 10-4 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver, and bone marrow. SPECT primary tumor-to-blood-pool ratios (T:BP) varied from 1.24 to 2.3 (mean, 1.79) at 1 h and 1.24 to 3.53 (mean, 2.22) at 2 h (P = 0.005). Two-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r = 0.68, P = 0.014). Two-hour T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs. 2.49, P = 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 13 patients. Conclusion: This first-in-human study demonstrates that 99mTc-labeled anti-PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2 h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.

Keywords: PD-L1; SPECT/CT; early phase I; non–small cell lung cancer; single domain antibody (sdAb).

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

FIGURE 1.
FIGURE 1.
Anterior whole-body images of patient at 10 min and 1, 2, 3, and 24 h after injection of 100 μg (group 1) (A) and 1- and 2-h images of a patient administered 400 μg of NM-01 (group 2) (B). No significant difference in biodistribution was seen between the 2 groups.
FIGURE 2.
FIGURE 2.
Time–activity curves for organs with highest radiotracer uptake.
FIGURE 3.
FIGURE 3.
(A) Left upper lobe tumor T:BP = 3.12 (PD-L1 expression 50%). (B) Left upper lobe tumor T:BP = 2.26 (PD-L1 expression 0%).
FIGURE 4.
FIGURE 4.
Left upper lobe tumor showing heterogeneity of PD-L1 expression. Central photopoenia is in keeping with necrosis, but there is heterogeneity of uptake in solid peripheral component of tumor (T:BP = 2.46, PD-L1 expression 85%).
FIGURE 5.
FIGURE 5.
Right upper lobe tumor (open arrows) shows areas of high 18F-FDG uptake (SUVmax = 16.1) on PET/CT (A) and 99mTc-SPECT/CT (T:BP = 3.53) (B). Mediastinal lymph nodes (closed arrows) show high 18F-FDG uptake (SUVmax = 6.3) (C) but low 99mTc-NM-01 activity (T:BP = 1.13) (D), demonstrating heterogeneity of PD-L1 expression between primary tumor and nodal sites of disease within same patient.
FIGURE 6.
FIGURE 6.
Coronal (A) and axial (B) 99mTc-NM-01 SPECT/CT images of a patient with skeletal metastases (arrows) demonstrating PD-L1 expression.

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Source: PubMed

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