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

Crittenden, M., Gough, M., Chester, John D. ORCID: https://orcid.org/0000-0002-7830-3840, 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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Abstract

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
URI:	https://orca.cardiff.ac.uk/id/eprint/18801

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