Quantitative PET imaging of PD-L1 expression in xenograft and syngeneic tumour models using a site-specifically labelled PD-L1 antibody

Abstract

Purpose Despite remarkable clinical responses and prolonged survival across several cancers, not all patients benefit from PD-1/ PD-L1 immune checkpoint blockade. Accordingly, assessment of tumour PD-L1 expression by immunohistochemistry (IHC) is increasingly applied to guide patient selection, therapeutic monitoring, and improve overall response rates. However, tissuebased methods are invasive and prone to sampling error. We therefore developed a PET radiotracer to specifically detect PD-L1 expression in a non-invasive manner, which could be of diagnostic and predictive value. Methods Anti-PD-L1 (clone 6E11, Genentech) was site-specifically conjugated with DIBO-DFO and radiolabelled with 89 Zr (89 Zr-DFO-6E11). 89 Zr-DFO-6E11 was optimized in vivo by longitudinal PET imaging and dose escalation with excess unlabelled 6E11 in HCC827 tumour-bearing mice. Specificity of 89 Zr-DFO-6E11 was evaluated in NSCLC xenografts and syngeneic tumour models with different levels of PD-L1 expression. In vivo imaging data was supported by ex vivo biodistribution, flow cytometry, and IHC. To evaluate the predictive value of 89 Zr-DFO-6E11 PET imaging, CT26 tumourbearing mice were subjected to external radiation therapy (XRT) in combination with PD-L1 blockade. Results 89 Zr-DFO-6E11 was successfully labelled with a high radiochemical purity. The HCC827 tumours and lymphoid tissue were identified by 89 Zr-DFO-6E11 PET imaging, and co-injection with 6E11 increased the relative tumour uptake and decreased the splenic uptake. 89 Zr-DFO-6E11 detected the differences in PD-L1 expression among tumour models as evaluated by ex vivo methods. 89 Zr-DFO-6E11 quantified the increase in PD-L1 expression in tumours and spleens of irradiated mice. XRT and anti-PD-L1 therapy effectively inhibited tumour growth in CT26 tumour-bearing mice (p < 0.01), and the maximum 89 Zr-DFO-6E11 tumour-to-muscle ratio correlated with response to therapy (p = 0.0252). Conclusion PET imaging with 89 Zr-DFO-6E11 is an attractive approach for specific, non-invasive, whole-body visualization of PD-L1 expression. PD-L1 expression can be modulated by radiotherapy regimens and 89 Zr-DFO-6E11 PET is able to monitor these changes and predict the response to therapy in an immunocompetent tumour model.

The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

“…Similar results have been proven also by Christensen et al [ 70 ]. Authors studied the efficacy of the anti-PD-L1 (clone 6E11) conjugated with dibenzocyclooctyne-Desferrioxamine (DIBO-DFO) chelator and radiolabelled with [ 89 Zr] ([ 89 Zr]DFO-6E11) on NSCLC xenografts and syngeneic tumors models with different levels of PD-L1 in CT26 tumor-bearing mice subjected to external radiation therapy (XRT) in combination with PD-L1 blockade.…”

Cerenkov luminescence imaging is an effective preclinical tool for assessing colorectal cancer PD-L1 levels in vivo

“…Molecular imaging comprehensively detects PD-L1 expression in patients with tumors throughout the body, and analyzes the real-time dynamic analysis of possible changes in tumor PD-L1 expression during treatment. So far, many studies have used different radionuclides, such as ( 99 mTc, 68 Ga, 64 Cu, 89 Zr, and 18 F) to label PD-L1 monoclonal antibodies [20,21] or engineered PD-L1specific peptides [22][23][24] in preclinical and clinical research. Some researchers have even found that atezolizumab labeled with 89 Zr can predict the PFS and OS in patients better than the IHC-based core needle biopsy [21].…”

Cerenkov luminescence imaging is an effective preclinical tool for assessing colorectal cancer PD-L1 levels in vivo

“…Molecular imaging comprehensively detects PD-L1 expression in patients with tumors throughout the body, and analyzes the real-time dynamic analysis of possible changes in tumor PD-L1 expression during treatment. So far, many studies have used different radionuclides, such as ( 99 mTc , 68 Ga, 64 Cu, 89 Zr and 18 F) to label PD-L1 monoclonal antibodies [19,20] or engineered PD-L1 specific peptides [21][22][23] in preclinical and clinical research. Some researchers have even found that atezolizumab labeled with 89 Zr can predict the PFS and OS in patients better than the IHC-based core needle biopsy [20].…”