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

Abstract

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-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine ([(18)F]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 approximately 7 x 10(5) T cells in the spleen and 1 x 10(4) T cells in LNs. Quantification of transplanted T cells in the tumor was hampered by the sr39tk-independent trapping of [(18)F]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.

• Authors: Chengyi J Shu, Caius G Radu, Stephanie M Shelly, Dan D Vo, Robert Prins, Antoni Ribas, Michael E Phelps, Owen N Witte
• Journal: International immunology (Int Immunol) Vol. 21 Issue 2 Pg. 155-65 (Feb 2009) ISSN: 1460-2377 [Electronic] England
• PMID: 19106231 (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

• Immunodominant Epitopes
• Membrane Glycoproteins
• Pmel protein, mouse
• Receptors, Antigen, T-Cell, alpha-beta
• gp100 Melanoma Antigen

Topics

• Animals
• Female
• Gene Transfer Techniques
• Genes, Reporter (genetics, immunology)
• Immunodominant Epitopes (genetics, immunology, metabolism)
• Immunotherapy, Adoptive
• Melanoma, Experimental (immunology, pathology, therapy)
• Membrane Glycoproteins (genetics, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monitoring, Immunologic (trends)
• Positron-Emission Tomography (methods)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, metabolism)
• T-Cell Antigen Receptor Specificity (genetics)
• T-Lymphocytes (diagnostic imaging, immunology, metabolism)
• gp100 Melanoma Antigen