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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. ORCID:, 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: 19 Oct 2022 08:42

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