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International Immunology Advance Access published online on December 23, 2008
International Immunology, doi:10.1093/intimm/dxn133
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© The Author 2008. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Quantitative PET reporter gene imaging of CD8+ T cells specific for a melanoma-expressed self-antigen

Chengyi J. Shu1, Caius G. Radu2,3, Stephanie M. Shelly2, Dan D. Vo4, Robert Prins4,5, Antoni Ribas5,6,7, Michael E. Phelps2,3 and Owen N. Witte1,2,7,8

1 Department of Microbiology, Immunology and Molecular Genetics
2 Department of Molecular and Medical Pharmacology
3 Crump Institute for Molecular Imaging
4 Department of Surgery
5 Jonsson Comprehensive Cancer Center
6 Department of Medicine
7 University of California at Los Angeles Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
8 Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095-1662, USA

Correspondence to: Correspondence to: O. N. Witte; E-mail: owenw{at}microbio.ucla.edu

Adoptive transfer (AT) T-cell therapy provides significant clinical benefits in patients with advanced melanoma. However, approaches to non-invasively visualize the persistence of transferred T cells are lacking. We examined whether positron emission tomography (PET) can monitor the distribution of self-antigen-specific T cells engineered to express an herpes simplex virus 1 thymidine kinase (sr39tk) PET reporter gene. Micro-PET imaging using the sr39tk-specific substrate 9-[4-[18F]fluoro-3-(hydroxymethyl)-butyl]guanine ([18F]FHBG) enabled the detection of transplanted T cells in secondary lymphoid organs of recipient mice over a 3-week period. Tumor responses could be predicted as early as 3 days following AT when a >25-fold increase of micro-PET signal in the spleen and 2-fold increase in lymph nodes (LNs) were observed in mice receiving combined immunotherapy versus control mice. The lower limit of detection was ~7 x 105 T cells in the spleen and 1 x 104 T cells in LNs. Quantification of transplanted T cells in the tumor was hampered by the sr39tk-independent trapping of [18F]FHBG within the tumor architecture. These data support the feasibility of using PET to visualize the expansion, homing and persistence of transferred T cells. PET may have significant clinical utility by providing the means to quantify anti-tumor T cells throughout the body and provide early correlates for treatment efficacy.

Keywords: cancer, immunotherapy, T lymphocytes

Transmitting editor: J. P. Allison

Received 10 June 2008, accepted 21 November 2008.


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