First-in-Humans Evaluation of a PD-L1–Binding Peptide PET Radiotracer in Non–Small Cell Lung Cancer Patients

Abstract

<b>Background:</b>⁶⁸Ga-NOTA-WL12 is a peptide-based positron emission tomography (PET) imaging agent. We conducted a first-in-human study of ⁶⁸Ga-NOTA-WL12 for PET to study the in vivo biodistribution, metabolism, radiation dosimetry, safety, and potential for quantifying programmed death ligand-1 (PD-L1) expression levels in advanced non-small cell lung cancer (NSCLC) patients. <b>Methods:</b> In vitro assessment of the relationship between PD-L1 expression and cellular uptake of ⁶⁸Ga-NOTA-WL12 was performed, followed by in vivo evaluation of ⁶⁸Ga-NOTA-WL12 uptake in animal models. Nine NSCLC patients with positive PD-L1 expression in lesions were enrolled. ⁶⁸Ga-NOTA-WL12 and paired ¹⁸F-FDG PET/CT imaging were performed. The patients were monitored for adverse events. The uptake (SUV/L and kBq/mL) values of tumors and normal organs were obtained. The biodistribution, radiation dosimetry and relationship of tumor uptake and PD-L1 expression were then evaluated. Follow-up ¹⁸F-FDG PET/CT was performed in patients who had undergone treatment with a combination of pembrolizumab with chemotherapy. <b>Results:</b> The cellular and animal experiments demonstrated that PD-L1 expression correlated with the uptake of ⁶⁸Ga-NOTA-WL12, and PD-L1-positive tumors exhibited high uptake of ⁶⁸Ga-NOTA-WL12. Clinical research showed that ⁶⁸Ga-NOTA-WL12 PET imaging is safe with acceptable radiation dosimetry. Physiological tracer uptake was mainly visible in the liver, spleen, small intestine and kidney. High contrast of tumors was observed, particularly in the lungs with a T/lung ratio of 4.45 ±1.89 at 1 h. One hour was a suitable timepoint for image acquisition because no significant differences were noted in the tumor-to-background ratios between 1 and 2 h. Additionally, a strong relationship was found between the tumor uptake (SUVpeak) and PD-L1 immunohistochemistry results (r = 0.9349; <i>P</i> = 0.002). ⁶⁸Ga-NOTA-WL12 uptake before therapy might indicate the therapeutic efficacy of pembrolizumab plus chemotherapy combination treatment. <b>Conclusion:</b> Our first-in-human findings demonstrate the safety and feasibility of ⁶⁸Ga-NOTA-WL12 for noninvasive in vivo detection of the tumor PD-L1 expression levels, indicating potential benefits for clinical PD-L1 therapy.

Topics & Concepts