Quantitative PET reporter gene imaging of CD8+ T cells specific for a melanoma-expressed self-antigen.
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.
Shu
Chengyi J
CJ
Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA 90095-1662, USA.
Radu
Caius G
CG
Shelly
Stephanie M
SM
Vo
Dan D
DD
Prins
Robert
R
Ribas
Antoni
A
Phelps
Michael E
ME
Witte
Owen N
ON
D000818:Animals; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics* / Q000276:immunology; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015166:Monitoring, Immunologic / Q000639:trends; D049268:Positron-Emission Tomography / Q000379:methods*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013601:T-Lymphocytes / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism*; D058951:gp100 Melanoma Antigen
D016056:Immunodominant Epitopes; D008562:Membrane Glycoproteins; C548642:Pmel protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D058951:gp100 Melanoma Antigen