In-depth characterization of a TCR-specific tracer for sensitive detection of tumor-directed transgenic T cells by immuno-PET

Nahid Yusufi, Sabine Mall, Henrique de Oliveira Bianchi, Katja Steiger, Sybille Reder, Richard Klar, Stefan Audehm, Mona Mustafa, Stephan Nekolla, Christian Peschel, Markus Schwaiger, Angela M. Krackhardt, Calogero D'Alessandria

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2402-2416
Number of pages15
JournalTheranostics
Volume7
Issue number9
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Cancer immunotherapy
  • Immuno-PET
  • In vivo T-cell imaging
  • T-cell quantification
  • T-cell receptor (TCR)-transgenic T cells

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