Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Program death-ligand 1 (PD-L1) and its corresponding receptor (PD-1) are the target of most FDA-approved ICIs. Perhaps unsurprisingly, PD-L1 levels are predictive of response to targeting drugs in lung and other cancers. However, PD-L1 is not predictive in other tumor types including renal cell carcinoma (RCC). PD-L1 is typically measured on tumor biopsies or archival tissues and we hypothesized that the lack of PD-L1 predictive power is due to tumor heterogeneity and tumor evolution. To test this notion, we embarked upon the generation of a PD-L1 probe that would enable real time assessment of PD-L1 across sites of disease using molecular imaging. We leveraged atezolizumab, a highly specific PD-L1 therapeutic antibody with a mutant Fc. Atezolizumab (ATZ) was labeled with 89Zr after conjugation with a bifunctional chelator and evaluated by positron emission tomography (PET). In extensive preclinical studies using multiple patient-derived xenografts (PDXs) with variable PD-L1 levels, we show that 89Zr-ATZ PET is able to distinguish RCC with variable PD-L1 expression. These data set the foundation for an investigator new drug (IND) approval from the FDA and an ongoing clinical trial in RCC patients (NCT04006522). Consistent with our hypothesis, 89Zr-ATZ PET shows substantial PD-L1 heterogeneity not only across but also within patients at different sites of disease. Furthermore, preliminary data suggest that PD-L1 levels may be predictive of response to ICI. By assessing PD-L1 expression in real time, 89Zr-ATZ PET may enable: (1) the identification of patients most likely to respond to PD-L1/PD-1 targeted therapies; (2) tailored management of the disease across different sites; (3) the evaluation of interventions that modulate PD-L1 levels; (4) insights into toxicities; and (5) probing resistance.
Citation Format: Aditi Mulgaonkar, Layton Woolford, Roy Elias, Kien Nham, Bing Guan, Guiyang Hao, Christina Stevens, Vanina Toffessi Tcheuyap, Sydney Haldeman, Jeffrey Miyata, Deyssy Carrillo, Qian (Janie) Qin, Nirmish Singla, Isaac Bowman, Jeffrey Cadeddu, Vitaly Margulis, Alana Christie, Payal Kapur, Ivan Pedrosa, Marianna Dakanali, Orhan Oz, Xiankai Sun, James Brugarolas. PD-L1 PET: A potential biomarker of checkpoint inhibitor sensitivity in renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1234.