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

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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.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants P01 CA59350, P50 CA86438, HL53752, CA76117, R24 CA83084, Department of Energy grants FG02-02ER63481, FG03-86ER60407, and 95ER62039, a Translational Research Award of the Leukemia and Lymphoma Society, the Aubrey Fund for Pediatric Cancer Research, the Larry H. Smead Fund, and the Vincent Astor Chair Research Fund.

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Authors and Affiliations

  1. Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, USA

    Pat Zanzonico

  2. Allogeneic Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Guenther Koehne, Ekaterina Doubrovina & Richard J. O’Reilly

  3. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Guenther Koehne, Ekaterina Doubrovina, Isabelle Riviere, Richard J. O’Reilly & Michel Sadelain

  4. Gene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Humilidad F. Gallardo, Isabelle Riviere & Michel Sadelain

  5. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mikhail Doubrovin, Ronald G. Blasberg & Steven M. Larson

  6. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mikhail Doubrovin & Ronald G. Blasberg

  7. Radiochemistry and Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Ronald Finn

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  1. Pat Zanzonico
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  2. Guenther Koehne
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Correspondence to Pat Zanzonico.

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Zanzonico, P., Koehne, G., Gallardo, H.F. et al. [131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity. Eur J Nucl Med Mol Imaging 33, 988–997 (2006). https://doi.org/10.1007/s00259-005-0057-3

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  • DOI: https://doi.org/10.1007/s00259-005-0057-3

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