Original article

European Journal of Nuclear Medicine and Molecular Imaging

, Volume 33, Issue 9, pp 988-997

First online:

[131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity

  • Pat ZanzonicoAffiliated withDepartment of Medical Physics, Memorial Sloan-Kettering Cancer Center Email author 
  • , Guenther KoehneAffiliated withAllogeneic Transplantation Service, Memorial Sloan-Kettering Cancer CenterImmunology Program, Memorial Sloan-Kettering Cancer Center
  • , Humilidad F. GallardoAffiliated withGene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center
  • , Mikhail DoubrovinAffiliated withDepartment of Radiology, Memorial Sloan-Kettering Cancer CenterDepartment of Neurology, Memorial Sloan-Kettering Cancer Center
  • , Ekaterina DoubrovinaAffiliated withAllogeneic Transplantation Service, Memorial Sloan-Kettering Cancer CenterImmunology Program, Memorial Sloan-Kettering Cancer Center
  • , Ronald FinnAffiliated withRadiochemistry and Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center
  • , Ronald G. BlasbergAffiliated withDepartment of Radiology, Memorial Sloan-Kettering Cancer CenterDepartment of Neurology, Memorial Sloan-Kettering Cancer Center
  • , Isabelle RiviereAffiliated withImmunology Program, Memorial Sloan-Kettering Cancer CenterGene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center
  • , Richard J. O’ReillyAffiliated withAllogeneic Transplantation Service, Memorial Sloan-Kettering Cancer CenterImmunology Program, Memorial Sloan-Kettering Cancer Center
    • , Michel SadelainAffiliated withImmunology Program, Memorial Sloan-Kettering Cancer CenterGene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center
    • , Steven M. LarsonAffiliated withDepartment of Radiology, Memorial Sloan-Kettering Cancer Center

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Abstract

Purpose

Donor T cells have been shown to be reactive against and effective in adoptive immunotherapy of Epstein-Barr virus (EBV) lymphomas which develop in some leukemia patients post marrow transplantation. These T cells may be genetically modified by incorporation of a replication-incompetent viral vector (NIT) encoding both an inactive mutant nerve growth factor receptor (LNGFR), as an immunoselectable surface marker, and a herpes simplex virus thymidine kinase (HSV-TK), rendering the cells sensitive to ganciclovir. The current studies are based on the selective HSV-TK-catalyzed trapping (phosphorylation) of the thymidine analog [131I]-2′-fluoro-2′-deoxy-1-β-D-arabinofuransyl-5-iodo-uracil (FIAU) as a means of stably labeling such T cells for in vivo trafficking (including tumor targeting) studies. Because of the radiosensitivity of lymphocytes and the potentially high absorbed dose to the nucleus from intracellular 131I (even at tracer levels), the nucleus absorbed dose (D n ) and dose-dependent immune functionality were evaluated for NIT+ T cells labeled ex vivo in [131I]FIAU-containing medium.

Methods

Based on in vitro kinetic studies of [131I]FIAU uptake by NIT+ T cells, D n was calculated using an adaptation of the MIRD formalism and the recently published MIRD cellular S factors. Immune cytotoxicity of [131I]FIAU-labeled cells was assayed against 51Cr-labeled target cells [B-lymphoblastoid cells (BLCLs)] in a standard 4-h release assay.

Results and conclusion

At median nuclear absorbed doses up to 830 cGy, a 51Cr-release assay against BLCLs showed no loss of immune cytotoxicity, thus demonstrating the functional integrity of genetically transduced, tumor-reactive T cells labeled at this dose level for in vivo cell trafficking and tumor targeting studies.

Keywords

Molecular imaging Radiobiology/dosimetry Radiopharmaceuticals Cell labeling Cell trafficking