In-depth Characterization of a TCR-specific Tracer for Sensitive Detection of Tumor-directed Transgenic T Cells by Immuno-PET
| Autor: | Stephan G. Nekolla, Sybille Reder, Markus Schwaiger, Calogero D'Alessandria, Henrique de Oliveira Bianchi, Mona Mustafa, Angela M. Krackhardt, Stefan Audehm, Sabine Mall, Nahid Yusufi, Katja Steiger, Richard Klar, Christian Peschel |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Transgene medicine.medical_treatment Receptors Antigen T-Cell Medicine (miscellaneous) Mice SCID Immunotherapy Adoptive 03 medical and health sciences Cancer immunotherapy Antigen Mice Inbred NOD In vivo Neoplasms medicine Animals Humans Pharmacology Toxicology and Pharmaceutics (miscellaneous) In vivo T-cell imaging cancer immunotherapy T-cell quantification Chemistry T-cell receptor (TCR)-transgenic T cells T-cell receptor Immunotherapy Molecular biology In vitro ddc Disease Models Animal 030104 developmental biology Positron-Emission Tomography immuno-PET Ex vivo Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.17994 |
| Popis: | A number of different technologies have been developed to monitor in vivo the distribution of gene-modified T cells used in immunotherapy. Nevertheless, in-depth characterization of novel approaches with respect to sensitivity and clinical applicability are so far missing. We have previously described a novel method to track engineered human T cells in tumors using 89Zr-Df-aTCRmu-F(ab')2 targeting the murinized part of the TCR beta domain (TCRmu) of a transgenic TCR. Here, we performed an in-depth in vitro characterization of the tracer in terms of antigen affinity, immunoreactivity, influence on T-cell functionality and stability in vitro and in vivo. Of particular interest, we have developed diverse experimental settings to quantify TCR-transgenic T cells in vivo. Local application of 89Zr-Df-aTCRmu-F(ab')2-labeled T cells in a spot-assay revealed signal detection down to approximately 1.8x104 cells. In a more clinically relevant model, NSG mice were intravenously injected with different numbers of transgenic T cells, followed by injection of the 89Zr-Df-aTCRmu-F(ab')2 tracer, PET/CT imaging and subsequent ex vivo T-cell quantification in the tumor. Using this setting, we defined a comparable detection limit of 1.0x104 T cells. PET signals correlated well to total numbers of transgenic T cells detected ex vivo independently of the engraftment rates observed in different individual experiments. Thus, these findings confirm the high sensitivity of our novel PET/CT T-cell tracking method and provide critical information about the quantity of transgenic T cells in the tumor environment suggesting our technology being highly suitable for further clinical translation. |
| Databáze: | OpenAIRE |
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