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Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy

Crittenden, M., Gough, M., Chester, John D., Kottke, T., Thompson, J., Ruchatz, A., Clackson, T., Cosset, F. L., Chong, H., Diaz, R. M., Harrington, K., Alvarez-Vallina, L. and Vile, R. 2003. Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy. Cancer Research 63 (12) , pp. 3173-3180.

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Last Modified: 04 Jun 2017 03:15

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