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


Authors: Zanzonico, P.; Koehne, G.; Gallardo, H. F.; Doubrovin, M.; Doubrovina, E.; Finn, R.; Blasberg, R. G.; Riviere, I.; O'Reilly, R. J.; Sadelain, M.; Larson, S. M.
Article Title: [131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: Cell-level dosimetry and dose-dependent toxicity
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. © Springer-Verlag 2006.
Keywords: controlled study; leukemia; unclassified drug; dose response; nonhuman; drug targeting; radiopharmaceuticals; mutant protein; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; metabolism; mouse mutant; animals; mice; animal tissue; cell function; cancer immunotherapy; intracellular transport; in vivo study; cytotoxicity; in vitro study; mice, scid; enzyme activity; molecular imaging; phosphorylation; radiation exposure; radiation response; dose-response relationship, radiation; genetic transduction; transduction, genetic; immunology; blood disease; hematologic neoplasms; dna modification; iodine 131; diagnostic agent; radioactive iodine; drug uptake; isotope labeling; iodine radioisotopes; dosimetry; lymphoma; radiopharmaceutical agent; drug derivative; uracil arabinoside; scintiscanning; arabinofuranosyluracil; drug clearance; radiosensitivity; target cell; cytotoxicity, immunologic; fialuridine; thymidine kinase; virus infection; immune function test; tracer; bone marrow transplantation; ex vivo study; cell level; drug sensitivity; herpes simplex virus; dose calculation; ganciclovir; adoptive immunotherapy; immunotherapy, adoptive; epstein barr virus; internalization; cell labeling; virus vector; epstein-barr virus infections; mathematical analysis; nerve growth factor receptor; radioiodination; virus enzyme; thymidine derivative; cell based gene therapy; b lymphoblast; lymphoblastoid cell; cell trafficking; chromium 51; radiobiology/dosimetry; fialuridine i 131; lymphocyte surface marker; b lymphoblastoid cell; function test; immunocytotoxicity
Journal Title: European Journal of Nuclear Medicine and Molecular Imaging
Volume: 33
Issue: 9
ISSN: 1619-7070
Publisher: Springer  
Date Published: 2006-09-01
Start Page: 988
End Page: 997
Language: English
DOI: 10.1007/s00259-005-0057-3
PUBMED: 16607546
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 10" - "Export Date: 4 June 2012" - "CODEN: EJNMA" - "Source: Scopus"
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MSK Authors
  1. Ronald G Blasberg
    244 Blasberg
  2. Ronald D Finn
    252 Finn
  3. Guenther Koehne
    175 Koehne
  4. Pat B Zanzonico
    246 Zanzonico
  5. Michel W J Sadelain
    462 Sadelain
  6. Isabelle C Riviere
    168 Riviere
  7. Steven M Larson
    779 Larson
  8. Richard O'Reilly
    487 O'Reilly