Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 45, Issue 1, Pages 110-120Publisher
SPRINGER
DOI: 10.1007/s00259-017-3803-4
Keywords
Nivolumab; Programmed cell death 1 (PD-1); Positron emission tomography (PET); Immunotherapy; Immune checkpoint inhibitor; immunoPET
Funding
- University of Wisconsin - Madison
- National Institutes of Health [NIBIB/NCI 1R01CA169365, 1R01CA205101, 1R01EB021336, T32CA009206, T32GM008505, 5T32GM08349, P30CA014520]
- National Science Foundation [DGE-1256259]
- American Cancer Society [125246-RSG-13-099-01-CCE]
- National Science Foundation of China [81401465, 51573096]
- Basic Research Program of Shenzhen [JCYJ20170412111100742, JCYJ20160422091238319]
- NATIONAL CANCER INSTITUTE [T32CA009206, R01CA205101, R01CA169365, P30CA014520] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB021336] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008505, T32GM007215, T32GM008349] Funding Source: NIH RePORTER
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Nivolumab is a human monoclonal antibody specific for programmed cell death-1 (PD-1), a negative regulator of T-cell activation and response. Acting as an immune checkpoint inhibitor, nivolumab binds to PD-1 expressed on the surface of many immune cells and prevents ligation by its natural ligands. Nivolumab is only effective in a subset of patients, and there is limited evidence supporting its use for diagnostic, monitoring, or stratification purposes. Zr-89-Df-nivolumab was synthesized to map the biodistribution of PD-1-expressing tumor infiltrating T-cells in vivo using a humanized murine model of lung cancer. The tracer was developed by radiolabeling the antibody with the positron emitter zirconium-89 (Zr-89). Imaging results were validated by ex vivo biodistribution studies, and PD-1 expression was validated by immunohistochemistry. Data obtained from PET imaging were used to determine human dosimetry estimations. The tracer showed elevated binding to stimulated PD-1 expressing T-cells in vitro and in vivo. PET imaging of Zr-89-Df-nivolumab allowed for clear delineation of subcutaneous tumors through targeting of localized activated T-cells expressing PD-1 in the tumors and salivary glands of humanized A549 tumor-bearing mice. In addition to tumor uptake, salivary and lacrimal gland infiltration of T-cells was noticeably visible and confirmed via histological analysis. These data support our claim that PD-1-targeted agents allow for tumor imaging in vivo, which may assist in the design and development of new immunotherapies. In the future, noninvasive imaging of immunotherapy biomarkers may assist in disease diagnostics, disease monitoring, and patient stratification.
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