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

Eur J Nucl Med Mol Imaging. 2018 Jan;45(1):110-120. doi: 10.1007/s00259-017-3803-4. Epub 2017 Aug 19.

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacokinetics*
  • Cells, Cultured
  • Humans
  • Leukemic Infiltration / diagnostic imaging*
  • Leukemic Infiltration / pathology
  • Lung / diagnostic imaging
  • Lung / pathology
  • Lung Neoplasms / diagnostic imaging*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nivolumab
  • Positron-Emission Tomography / methods*
  • Programmed Cell Death 1 Receptor / metabolism
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics*
  • T-Lymphocytes / metabolism*
  • Tissue Distribution
  • Zirconium / chemistry*

Substances

  • Antibodies, Monoclonal
  • Programmed Cell Death 1 Receptor
  • Radiopharmaceuticals
  • Nivolumab
  • Zirconium