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

Abstract

Background: 68 Ga-NOTA-WL12 is a peptide-based positron emission tomography (PET) imaging agent. We conducted a first-in-human study of 68 Ga-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. Methods: In vitro assessment of the PD-L1 expression and cellular uptake of 68 Ga-NOTA-WL12 were performed, followed by in vivo evaluation of 68 Ga-NOTA-WL12 uptake in mouse models with tumors. Nine NSCLC patients with lesions expressing PD-L1 were enrolled and monitored for adverse events during the study. 68 Ga-NOTA-WL12 and paired 18 F-FDG PET/CT imaging were performed. Uptake (SUV/L and kBq/mL) values of tumors and normal organs were obtained.Radiopharmaceutical biodistribution, radiation dosimetry and the relationship of tumor uptake to PD-L1 expression were evaluated. Follow-up 18 F-FDG PET/CT was performed in patients who had undergone treatment with a combination of pembrolizumab with chemotherapy. Results: 68 Ga-NOTA-WL12 exhibited PD-L1 specific uptake in vitro and in PD-L1-positive tumors in vivo. 68 Ga-NOTA-WL12 PET imaging proved safe with acceptable radiation dosimetry. Physiological tracer uptake was mainly visible in the liver, spleen, small intestine and kidney. Tumors were clearly visible, particularly in the lungs, with a T/lung ratio of 4.45 ±1.89 at 1 h. One hour was a suitable time-point for image acquisition because no significant differences were noted in tumor-to-background ratios between 1 and 2 h. A strong, positive correlation was found between tumor uptake (SUVpeak) and PD-L1 immunohistochemistry results (r = 0.9349; P = 0.002). 68 Ga-NOTA-WL12 and 18 F-FDG PET studies suggest that PD-L1 PET before therapy may indicate the therapeutic efficacy of pembrolizumab plus chemotherapy combination treatment. Conclusions: Our first-in-human findings demonstrate the safety and feasibility of 68 Ga-NOTA-WL12 for noninvasive, in vivo detection of tumor PD-L1 expression levels, indicating potential benefits for clinical PD-L1 therapy.

Preclinical and exploratory human studies of novel 68Ga-labeled D-peptide antagonist for PET imaging of TIGIT expression in cancers

“…S1 ). The preparation of 68 Ga-labeled D-peptides was accomplished according to the reported methods [ 21 , 24 ]. The radiosynthesis and characterization including radiochemical yield, radiochemical purity, molar activity, partition coefficient, in vitro and in vivo stability were described in Supplemental Information.…”

“…This is exemplified by the observation that PD-L1 negative tumors have responded to anti-PD-1/PD-L1 treatment [18]. Fortunately, the use of positron emission tomography (PET) as an in vivo imaging method to quantify PD-1/PD-L1 expression has demonstrated a better relevance with therapy response than IHC in clinical trials [19][20][21][22]. This instigated research in PET imaging of TIGIT expression for the stratification of patients.…”

Preclinical and Exploratory Clinical Studies of Novel 68Ga-labeled ᴅ-Peptide Antagonist for PET Imaging of TIGIT Expression in Cancers

“…S1-4). Details of 68 Ga-labeledpeptides preparation were described in Supplemental Information following the general methods [21,24].…”

“…This is exempli ed by the observation that PD-L1 negative tumors have responded to anti-PD-1/PD-L1 treatment [18]. Fortunately, the use of positron emission tomography (PET) as an in vivo imaging method to quantify PD-1/PD-L1 expression has demonstrated a better relevance with therapy response than IHC in clinical trials [19][20][21][22]. This instigated research in PET imaging of TIGIT expression for the strati cation of patients.…”

Current status and future perspective of radiopharmaceuticals in China

“…Huang et al tested the new immuno-PET probe [ 124 I]I-JS001 to verify its potential in PD1-positive tumors patients [58]. Yang's group also conducted a first-in-human study of [ 68 Ga]Ga-NOTA-WL12 (a PD-L1-binding peptide radiotracer) demonstrating the safety and feasibility of the tracer for the detection of the tumor PD-L1 expression levels [59].…”