[131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity
| Autor: | Michel Sadelain, Humilidad F. Gallardo, Richard J. O'Reilly, Steven M. Larson, Mikhail Doubrovin, Guenther Koehne, Isabelle Riviere, Ekaterina Doubrovina, Ronald D. Finn, Ronald G. Blasberg, Pat Zanzonico |
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| Rok vydání: | 2006 |
| Předmět: |
Cytotoxicity
Immunologic Epstein-Barr Virus Infections T-Lymphocytes medicine.medical_treatment Mice SCID In Vitro Techniques Immunotherapy Adoptive Viral vector Iodine Radioisotopes Mice Immune system Transduction Genetic In vivo medicine Animals Humans Radiology Nuclear Medicine and imaging Radiosensitivity Radionuclide Imaging Cytotoxicity Chemistry Arabinofuranosyluracil Dose-Response Relationship Radiation General Medicine Immunotherapy Virology Molecular biology Thymidine kinase Hematologic Neoplasms Radiopharmaceuticals Ex vivo |
| Zdroj: | European Journal of Nuclear Medicine and Molecular Imaging. 33:988-997 |
| ISSN: | 1619-7089 1619-7070 |
| Popis: | 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. 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. 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. |
| Databáze: | OpenAIRE |
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