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

Purpose: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell car-cinoma (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 IHC in an RCC patient-derived tumor-graft (TG) platform.Experimental Design: Eight independent RCC TGs with a wide range of PD-L1 expression (0%-85%) were evaluated by immuno-PET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ)was compared with 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 pXY = 0.78). Further-more, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corre-sponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness.Conclusions: ImmunoPET with [89Zr]Zr-DFO-ATZ may enable athorough 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).