Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy.
We aimed to use cell-based carriers to direct vector production to target sites for systemic therapy. We used T cells engineered to express a chimeric T cell receptor that can specifically recognize target cells expressing the tumor-associated carcinoembryonic antigen (CEA). These T cells were modified to produce a retrovirus under tight pharmacological control using the rapamycin-inducible transcriptional regulatory system. The retroviral vectors produced were transcriptionally targeted to CEA-expressing target cells. We found that vector production and transgene expression from these T cells in vitro was dependent on pharmacological induction and expression of CEA in target cells, respectively. Mice bearing metastatic tumors that received cell carriers delivering the HSVtk gene demonstrated a significant increase in survival, but only in response to pharmacological induction of vector production. Interestingly, the therapeutic effect required the presence of the tumor-specific chimeric receptor on T cells. Further studies demonstrated that systemic delivery of tumor-specific T cells to mice bearing metastatic tumors caused recruitment of nonspecific T cells to the tumor site. We hypothesize that this enhanced targeting to tumor sites is responsible for the efficiency of T cell-mediated retroviral gene transfer and that this principle can be used to enhance systemic therapies using immune-cell carriers.
Crittenden
Marka
M
Department of Immunology and Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
Gough
Michael
M
Chester
John
J
Kottke
Tim
T
Thompson
Jill
J
Ruchatz
Anja
A
Clackson
Tim
T
Cosset
Francois Luic
FL
Chong
Heung
H
Diaz
Rosa Maria
RM
Harrington
Kevin
K
Alvarez Vallina
Luis
L
Vile
Richard
R
D000230:Adenocarcinoma / Q000473:pathology / Q000556:secondary; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000473:pathology; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes; D015967:Gene Expression Regulation, Viral; D005813:Genes, Synthetic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells / Q000637:transplantation / Q000821:virology*; D008114:Liver Neoplasms, Experimental / Q000556:secondary / Q000628:therapy; D008545:Melanoma / Q000473:pathology / Q000556:secondary; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics* / Q000502:physiology; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D020079:Terminal Repeat Sequences; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014161:Transduction, Genetic; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D005456:Fluorescent Dyes; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D013937:Thymidine Kinase; D020123:Sirolimus