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89Zr-labeled nivolumab for imaging of T-cell infiltration in a humanized murine model of lung cancer

  • Christopher G. England
  • Dawei Jiang
  • Emily B. Ehlerding
  • Brian T. Rekoske
  • Paul A. Ellison
  • Reinier Hernandez
  • Todd E. Barnhart
  • Douglas G. McNeel
  • Peng Huang
  • Weibo Cai
Original Article

Abstract

Purpose

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.

Methods

89Zr-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 (89Zr). 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.

Results

The tracer showed elevated binding to stimulated PD-1 expressing T-cells in vitro and in vivo. PET imaging of 89Zr-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.

Conclusions

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.

Keywords

Nivolumab Programmed cell death 1 (PD-1) Positron emission tomography (PET) Immunotherapy Immune checkpoint inhibitor immunoPET 

Notes

Acknowledgements

This work was supported, in part, by the University of Wisconsin - Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, 1R01CA205101, 1R01EB021336, T32CA009206, T32GM008505, 5T32GM08349, P30CA014520), the National Science Foundation (DGE-1256259), the American Cancer Society (125246-RSG-13-099-01-CCE), the National Science Foundation of China (81401465, 51573096), and the Basic Research Program of Shenzhen (JCYJ20170412111100742, JCYJ20160422091238319).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2017_3803_MOESM1_ESM.docx (14 kb)
ESM 1 (DOCX 14 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Christopher G. England
    • 1
  • Dawei Jiang
    • 2
    • 3
  • Emily B. Ehlerding
    • 1
  • Brian T. Rekoske
    • 4
  • Paul A. Ellison
    • 1
  • Reinier Hernandez
    • 1
  • Todd E. Barnhart
    • 1
  • Douglas G. McNeel
    • 4
    • 5
  • Peng Huang
    • 2
  • Weibo Cai
    • 1
    • 3
    • 5
  1. 1.Department of Medical PhysicsUniversity of Wisconsin – MadisonMadisonUSA
  2. 2.Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical EngineeringHealth Science Center, Shenzhen UniversityGuangzhouPeople’s Republic of China
  3. 3.Department of RadiologyUniversity of Wisconsin – MadisonMadisonUSA
  4. 4.Department of MedicineUniversity of Wisconsin – MadisonMadisonUSA
  5. 5.University of Wisconsin Carbone Cancer CenterMadisonUSA

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