Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells.
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.
Chester
John
J
Molecular Medicine Program, Guggenheim 18, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
Ruchatz
Anja
A
Gough
Michael
M
Crittenden
Marka
M
Chong
Heung
H
Cosset
François-Loïc
FL
Loïc-Cosset
François
F
Diaz
Rosa Maria
RM
Harrington
Kevin
K
Alvarez-Vallina
Luis
L
Vile
Richard
R
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
D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins