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T cells redirected by a CD3ζ chimeric antigen receptor can establish self-antigen-specific tumour protection in the long term

Gene Therapy volume 20, pages 177–186 (2013)Cite this article

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Abstract

A majority of cancer deaths are because of an uncontrolled relapse of the disease despite initial remission after therapy, asking for strategies to control tumour cells in the long term. Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed promising success in primary tumour elimination; the capacity of such engineered T cells to establish enduring tumour protection is currently a matter of discussion, in particular as most targeted ‘tumour-associated antigens’ are self-antigens. To address the issue in a clinically relevant model that closely mimics the human situation, we recorded rejection of carcinoembryonic antigen (CEA)-positive pancreatic tumours in the CEA transgenic mouse that expressed CEA as self-antigen in healthy cells of the gastrointestinal tract. Adoptive therapy with CD8+ T cells, which were redirected by a CEA-specific, low-affinity CAR with CD3ζ endodomain, eliminated CEA+ tumours in a primary response; cured mice produced an efficient recall response in the long term towards CEA+ tumour cells upon rechallenge. Secondary tumour rejection was CEA specific, mediated by engineered T cells and did not require host T cells. No toxicity towards healthy tissues with CEA expression was recorded. Data indicate that adoptive therapy with engineered T cells can establish self-antigen-specific tumour protection in the long term without autoimmunity.

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Acknowledgements

We thank Dr Inga Wedemeyer, Institute of Pathology, University Hospital Cologne, for re-evaluating tissue slides and Danuta Chrobok, Nicole Hoffmann, Frank Steiger and Samir Tawardos for technical assistance. This study was supported by grants from Deutsche Krebshilfe, Bonn, Germany; Else Kröner Fresenius-Stiftung, Homburg v.d.H., Germany; Deutsche Forschungsgemeinschaft, Bonn, Germany; and Fortune program of the Medical Faculty of the University of Cologne.

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  1. Centre for Molecular Medicine Cologne (CMMC) and Department of Internal Medicine I, University of Cologne, Cologne, Germany

    M Chmielewski, G Rappl, A A Hombach & H Abken

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  1. M Chmielewski
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  2. G Rappl
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  3. A A Hombach
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  4. H Abken
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Correspondence to H Abken.

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Chmielewski, M., Rappl, G., Hombach, A. et al. T cells redirected by a CD3ζ chimeric antigen receptor can establish self-antigen-specific tumour protection in the long term. Gene Ther 20, 177–186 (2013). https://doi.org/10.1038/gt.2012.21

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