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Tumor antigen–specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor–modified T cells

Nature Biotechnology volume 20, pages 256–263 (2002)Cite this article

A Corrigendum to this article was published on 01 October 2006

Abstract

High-level systemic delivery of viral vectors to tumors has proved problematic as a result of immune neutralization, nonspecific adhesion, and clearance of circulating viral particles. Some cell types localize to tumors in response to particular biological properties associated with tumor growth. Their use to deliver viral vectors to tumors would allow precious viral stocks to be protected until they can be released at high local concentrations. Here, we describe a mechanism by which retroviral vector production by T cells can be regulated by a tumor-specific trigger through engagement of a chimeric immune receptor (CIR) with its target antigen. The virus that is released from the T cells can also be transcriptionally targeted. Finally, we show that it is possible to use vector-loaded, antigen-triggered human T cells as therapeutic, tumor-specific vector delivery cells in models of both local intratumoral and systemic delivery to both lung and liver metastases. This strategy incorporates multiple levels of targeting into the delivery system at the stages of surface targeting, viral production, and gene expression.

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Figure 1: Retroviral vectors.
Figure 2: Antigen-specific induction of transcriptionally targeted GFP retrovirus from Jurkat T cells.
Figure 3: Antigen-specific induction of HSVtk-containing retroviral vectors leads to CEA+ selective tumor cell killing.
Figure 4: Retroviral production from Jurkat.CEA cells is optimal between 6 and 12 h following coculture with antigen-positive cells.
Figure 5: Human T cells can act as antigen-specific retroviral producer cells in vivo.

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Acknowledgements

The authors thank Toni L. Higgins for expert secretarial assistance. This work was supported by the Mayo Foundation and by the Association of Cancer Physicians of the United Kingdom (J.C). We are grateful to Dr. Carlos Paya of the Mayo Clinic for supplying the (NF-κB)3 promoter fragment.

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Author notes

  1. John Chester

    Present address: ICRF Oncology Unit, St. James University Hospital, Leeds, UK

  2. John Chester and Anja Ruchatz: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Medicine Program, Guggenheim 18, Mayo Clinic, 200 First Street SW, Rochester, MN, USA

    John Chester, Anja Ruchatz, Michael Gough, Marka Crittenden, Heung Chong, Rosa Maria Diaz, Kevin Harrington, Luis Alvarez-Vallina & Richard Vile

  2. Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, Lyon, Cedex 07, France

    François Loïc-Cosset

  3. Chester Beatty Laboratories, Fulham Road, London, UK

    Kevin Harrington

  4. Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, San Martín de Porres, 4, Madrid, Spain

    Luis Alvarez-Vallina

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Chester, J., Ruchatz, A., Gough, M. et al. Tumor antigen–specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor–modified T cells. Nat Biotechnol 20, 256–263 (2002). https://doi.org/10.1038/nbt0302-256

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