[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 [(131)I]-2'-fluoro-2'-deoxy-1-beta-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 (131)I (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 [(131)I]FIAU-containing medium.

METHODS:

Based on in vitro kinetic studies of [(131)I]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 [(131)I]FIAU-labeled cells was assayed against (51)Cr-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 (51)Cr-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.

• Authors: Pat Zanzonico, Guenther Koehne, Humilidad F Gallardo, Mikhail Doubrovin, Ekaterina Doubrovina, Ronald Finn, Ronald G Blasberg, Isabelle Riviere, Richard J O'Reilly, Michel Sadelain, Steven M Larson
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 33 Issue 9 Pg. 988-97 (Sep 2006) ISSN: 1619-7070 [Print] Germany
• PMID: 16607546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Iodine Radioisotopes
• Radiopharmaceuticals
• Arabinofuranosyluracil
• fialuridine

Topics

• Animals
• Arabinofuranosyluracil (analogs & derivatives, pharmacokinetics)
• Cytotoxicity, Immunologic
• Dose-Response Relationship, Radiation
• Epstein-Barr Virus Infections (diagnostic imaging, immunology, therapy)
• Hematologic Neoplasms (diagnostic imaging, immunology, therapy)
• Humans
• Immunotherapy, Adoptive
• In Vitro Techniques
• Iodine Radioisotopes (pharmacokinetics)
• Mice
• Mice, SCID
• Radionuclide Imaging
• Radiopharmaceuticals (pharmacokinetics)
• T-Lymphocytes (immunology, metabolism, radiation effects)
• Transduction, Genetic