Nature Biotechnology
20, 256 - 263 (2002)
doi:10.1038/nbt0302-256
There is a Corrigendum (October 2006) associated with this Article.
Tumor antigen−specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor−modified T cellsJohn Chester1, 2, 6, Anja Ruchatz1, 6, Michael Gough1, Marka Crittenden1, Heung Chong1, François Loïc-Cosset3, Rosa Maria Diaz1, Kevin Harrington1, 4, Luis Alvarez-Vallina1, 5
& Richard Vile11
Molecular Medicine Program, Guggenheim 18, Mayo Clinic, 200 First Street SW, Rochester, MN, USA. 2
Current address:ICRF Oncology Unit, St. James University Hospital, Leeds, UK. 3
Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, Lyon Cedex 07, France. 4
Chester Beatty Laboratories, Fulham Road, London, UK. 5
Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, San Martín de Porres, 4, Madrid, Spain. 6
These authors contributed equally to this work.
Correspondence should be addressed to Richard Vile richard.vile@mayo.eduHigh-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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