Cancer Immunology, Immunotherapy

, Volume 58, Issue 6, pp 977–987

Lentiviral vectors encoding human MUC1-specific, MHC-unrestricted single-chain TCR and a fusion suicide gene: potential for universal and safe cancer immunotherapy

Authors

  • Xiaochuan Chen
    • Department of ImmunologyUniversity of Pittsburgh School of Medicine
    • Garden State Cancer CenterCenter for Molecular Medicine and Immunology
  • Wentao Gao
    • Department of PathologyUniversity of Pittsburgh School of Medicine
  • Andrea Gambotto
    • Center for Biotechnology and Institute of Molecular MedicineUniversity of Pittsburgh School of Medicine
    • Department of ImmunologyUniversity of Pittsburgh School of Medicine
Original Article

DOI: 10.1007/s00262-008-0624-0

Cite this article as:
Chen, X., Gao, W., Gambotto, A. et al. Cancer Immunol Immunother (2009) 58: 977. doi:10.1007/s00262-008-0624-0

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.

Keywords

MUC1T cell receptor (TCR)Lentiviral vectorCancer immunotherapy

Copyright information

© Springer-Verlag 2008