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Monitoring the Efficacy of Adoptively Transferred Prostate Cancer–Targeted Human T Lymphocytes with PET and Bioluminescence Imaging

¹ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ² Immunology Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For correspondence or reprints contact: Vladimir Ponomarev, Molecular Imaging Laboratory, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 501, Z-2063, New York, NY 10021. E-mail: ponomarv{at}mskcc.org

Noninvasive imaging technologies have the potential to enhance the monitoring and improvement of adoptive therapy with tumor-targeted T lymphocytes. We established an imaging methodology for the assessment of spatial and temporal distributions of adoptively transferred genetically modified human T cells in vivo for treatment monitoring and prediction of tumor response in a systemic prostate cancer model. Methods: RM1 murine prostate carcinoma tumors transduced with human prostate-specific membrane antigen (hPSMA) and a Renilla luciferase reporter gene were established in SCID/beige mice. Human T lymphocytes were transduced with chimeric antigen receptors (CAR) specific for either hPSMA or human carcinoembryonic antigen (hCEA) and with a fusion reporter gene for herpes simplex virus type 1 thymidine kinase (HSV1tk) and green fluorescent protein, with or without click beetle red luciferase. The localization of adoptively transferred T cells in tumor-bearing mice was monitored with 2'-¹⁸F-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-ethyluracil (¹⁸F-FEAU) small-animal PET and bioluminescence imaging (BLI). Results: Cotransduction of CAR-expressing T cells with the reporter gene did not affect CAR-mediated cytotoxicity. BLI of Renilla and click beetle red luciferase expression enabled concurrent imaging of adoptively transferred T cells and systemic tumors in the same animal. hPSMA-specific T lymphocytes persisted longer than control hCEA-targeted T cells in lung hPSMA-positive tumors, as indicated by both PET and BLI. Precise quantification of T-cell distributions at tumor sites by PET revealed that delayed tumor progression was positively correlated with the levels of ¹⁸F-FEAU accumulation in tumor foci in treated animals. Conclusion: Quantitative noninvasive monitoring of genetically engineered human T lymphocytes by PET provides spatial and temporal information on T-cell trafficking and persistence. PET may be useful for predicting tumor response and for guiding adoptive T-cell therapy.

Key Words: PET • molecular imaging • adoptive immunotherapy • HSV1tk • ¹⁸F-FEAU

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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