ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables In Vivo Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma

Abstract

Purpose: Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno-positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to immunohistochemistry (IHC) in an RCC patient-derived tumorgraft (TG) platform. Experimental Design: Eight independent RCC TGs with a wide range of PD-L1 expression (0 – 85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared to PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC. Results: ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 post-injection) revealed a statistically significant association with PD-L1 IHC assays (p = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness. Conclusions: ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).

Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging in Radiation Therapy Treatment Planning: A Review of PET Imaging Tracers and Methods to Incorporate PET/CT

“…For example, there are tracers being developed to target DNA synthesis pathways, 58 , 59 , 60 , 61 , 62 , 63 , 64 angiogenesis, 65 , 66 , 67 , 68 apoptosis, 69 hypoxia, and even immuno-PET tracers with monoclonal antibodies targeting immune checkpoints or other immune system pathways. 70 , 71 Many of these tracers could guide dose painting and response adaptive treatment protocols in the future. The ability to target hypoxic regions of a tumor is especially appealing to an oncologist as hypoxia is known to reduce chemotherapeutic and radiotherapeutic efficacy of treatment.…”

PET Imaging of Peptide Probe Al[18F]F-NOTA-PCP1 for Monitoring the Engagement of PD-L1 Antibodies in Tumors

“…Furthermore, it is significant to noninvasively keep track of the real-time fluctuations in drug-target interactions. Positron emission tomography (PET) allows processes noninvasively to monitor different PD-L1 status in both tumor and metastatic foci. − More importantly, PET can visualize intratumoral and intercellular heterogeneity . Peptides are regarded as promising candidates for PET imaging because of their simple synthesis and favorable physicochemical characteristics, including their small molecular size and effective tissue permeability. − For instance, WL12 has been used for PET/CT imaging to detect the PD-L1 status of tumors.…”

“…Positron emission tomography (PET) allows processes noninvasively to monitor different PD-L1 status in both tumor and metastatic foci. 19 − 21 More importantly, PET can visualize intratumoral and intercellular heterogeneity. 22 Peptides are regarded as promising candidates for PET imaging because of their simple synthesis and favorable physicochemical characteristics, including their small molecular size and effective tissue permeability.…”

Scandium-44: Diagnostic Feasibility in Tumor-Related Angiogenesis

“…Given its favourable decay half-life (T 1/2 = 3.3 days; 78.4 h), appropriate radiochemistry, and the accessibility of different chelating agents for complexation with the radioisotope, 89 Zr is welcomed for the radiolabelling of PET-based imaging molecules [ 63 ]. The relatively long half-life of the radiometal could be easily adjusted to the pharmacokinetic profile of monoclonal antibodies (mABs); therefore, 89 Zr seems to be well suited for the radiolabelling of mABs and for PET immunoimaging applications [ 63 , 64 , 65 ]. Several mAbs, including anti-human epidermal growth factor receptor 2 (HER2) trastuzumab, anti-epidermal growth factor receptor (EGFR) mAb cetuximab, anti-PSMA mAb J591, and anti-vascular endothelial growth factor (VEGF) bevacizumab, were successfully labelled with 89 Zr for the PET imaging of breast cancer, squamous-cell carcinoma, prostate tumours, and ovarian tumours, respectively, at both preclinical and clinical levels [ 66 , 67 , 68 , 69 ].…”