Lentiviral vectors encoding human MUC1-specific,MHC-unrestricted single-chain TCR and a fusion suicide gene: potential for universal and safe cancer immunotherapy |
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Authors: | Xiaochuan Chen Wentao Gao Andrea Gambotto Olivera J Finn |
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Institution: | (1) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA;(2) Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Ave, Belleville, NJ 07109, USA;(3) Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;(4) Center for Biotechnology and Institute of Molecular Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA |
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Abstract: | MUC1 tumor antigen is a target for immunotherapy of most human adenocarcinomas and some hematological malignancies. Expression
of a MUC1-specific, MHC-unrestricted single-chain T cell receptor (scTCR) on cells of both innate and adaptive immune system
through reconstitution of lethally irradiated mice by retroviral vector-transduced bone marrow cells, had been shown to effectively
control the growth of MUC1+ tumors independent of their MHC type, suggesting that this receptor is a good candidate for broadly applicable gene therapy/immunotherapy.
However, the translational application of this immuno-gene therapy modality was discouraged by the progressive transgene silencing
in reconstituted T and B cells, as well as the potential of tumorogenesis intrinsic to oncoretroviral vectors. To overcome
these problems and facilitate the future clinical use of this receptor, we have constructed a panel of novel self-inactivating
lentiviral vectors (LVs) which harbor two independent internal promoters, one driving expression of the scTCR gene and the
other of a fusion suicide gene, the HSV-TK–EGFP fusion gene, allowing the transduced cells to be destroyable by the pro-drug
ganciclovir. Despite the large size of insert, these vectors were efficiently packaged into high titer virus that transferred
the expression of transgene in both T cell lines and primary T cells. Sustained expression was maintained in a T cell line
for over 4 months in vitro, suggesting its efficient resistance to transgene silencing. Both scTCR and HSV-TK–EGFP genes were
functional in the transduced cells, as evidenced by their specific recognition of MUC1+ tumors and efficient eradication by ganciclovir. |
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Keywords: | MUC1 T cell receptor (TCR) Lentiviral vector Cancer immunotherapy |
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