Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes

Abstract

New technologies are needed to characterize the migration, survival, and function of antigen-specific T cells in vivo. Here, we demonstrate that Epstein-Barr virus (EBV)--specific T cells transduced with vectors encoding herpes simplex virus-1 thymidine kinase (HSV-TK) selectively accumulate radiolabeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU). After adoptive transfer, HSV-TK+ T cells labeled in vitro or in vivo with [131I]FIAU or [124I]FIAU can be noninvasively tracked in SCID mice bearing human tumor xenografts by serial images obtained by scintigraphy or positron emission tomography (PET), respectively. These T cells selectively accumulate in EBV+ tumors expressing the T cells' restricting HLA allele but not in EBV- or HLA-mismatched tumors. The concentrations of transduced T cells detected in tumors and tissues are closely correlated with the concentrations of label retained at each site. Radiolabeled transduced T cells retain their capacity to eliminate targeted tumors selectively. This technique for imaging the migration of ex vivo-transduced antigen-specific T cells in vivo is informative, nontoxic, and potentially applicable to humans.

Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive In vivo Positron Emission Tomography Imaging

“…We use the term ''tracer cells'' in context of the potential future clinical scenario, in which the HSV1-TK-expressing hMSCs will be used to ''trace'' the coadministered therapeutic hMSCs genetically modified to express various anticancer cytokines (12,13). Similar PET imaging approach was applied in several recent studies for noninvasively visualization of HSV1-TK-expressing stem cells after direct intramyocardial injection (30,31) and for visualization of tumor targeting by the adoptively transferred tumor antigen-specific T cells (32,33). Another potential clinical therapeutic protocol, which would be greatly facilitated by noninvasive imaging, would include repetitive (e.g., biweekly or monthly) administration of HSV1-TK-expressing autologous stem cells to patients following resection of a primary tumor, which has high likelihood of metastases that are radiologically not detectable at the time of resection.…”

Utility of a Herpes Oncolytic Virus for the Detection of Neural Invasion by Cancer

“…Green fluorescent protein has previously been used as marker for retrovirus and herpes vector gene transfer into various cancers including brain, mesothelioma, and breast tumors [20,21]. Similar vectors were also used as molecular imaging modalities to target radioactive tracers into cancers [12,22]. In this study, we demonstrate the utility of viral vectors to detect cancer cells invading nerves through noninvasive PET imaging and real-time fluorescence imaging.…”

PET imaging of adoptive progenitor cell therapies.

“…A clinically applicable in vivo whole body PET imaging with 18F-FHBG was used to non-invasively monitor the fate of genetically modified HSVTK and eGFP expressing "tracer" hMSCs (TG-hMSCs) upon their intratumoral or intravenous administration. The term "tracer cells" is being used in context of the potential future clinical scenario, in which the HSVTK-expressing hMSCs will be used to "trace" the co-administered therapeutic hMSCs genetically modified to express various anti-cancer cytokines (58, 59) Similar PET imaging approach was applied in several recent studies for non-invasively visualization of HSVTK expressing stem cells after direct intra-myocardial injection (75,76), and for visualization of tumor targeting by the adoptively transferred tumor antigen-specific T cells (77,78). Another potential clinical therapeutic protocol, which would be greatly facilitated by non-invasive imaging, would include repetitive (e.g., bi-weekly or monthly) administration of HSV1-TK expressing autologous stem cells to patients following resection of a primary tumor which has high likelihood of metastases that are radiologically not detectable at the time of resection.…”