title: Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells.
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.
authors.affiliation: Molecular Medicine Program, Guggenheim 18, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
authors.forename: John
authors.initials: J
authors.lastname: Chester
authors.forename: Anja
authors.initials: A
authors.lastname: Ruchatz
authors.forename: Michael
authors.initials: M
authors.lastname: Gough
authors.forename: Marka
authors.initials: M
authors.lastname: Crittenden
authors.forename: Heung
authors.initials: H
authors.lastname: Chong
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: François
authors.initials: F
authors.lastname: Loïc-Cosset
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Diaz
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Vallina
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins