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Pharmacologically Regulated Production of Targeted Retrovirus from T Cells for Systemic Antitumor Gene Therapy¹

Department of Immunology [M. C.] and Molecular Medicine Program [M. C., M. G., J. C., T. K., J. T., A. R., H. C., R. M. D., K. H., R. V.], Mayo Clinic, Rochester, Minnesota; ARIAD Gene Therapeutics, Cambridge, Massachusetts [T. C.]; Vectorologie Retrovirale et Therapie Genique, INSERM U412, Lyon Cedex 07, France [F. L. C.]; and Hospital Universitario C/San Martin de Porres, Madrid, Spain [L. A. V.]

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.

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