ABSTRACT
Immunotherapy utilizing induced pluripotent stem cell (iPSC) technology has great potential. Functionally rejuvenated cytotoxic T lymphocytes (CTLs) can survive long-term as young memory T cells in vivo, with continuous tumor eradication. Banking of iPSCs as an unlimited "off-the-shelf" source of therapeutic T cells may be feasible. To generate safer iPSCs, we reprogrammed human papilloma virus type 16 (HPV16) E6-specific CTLs by Sendai virus vector without cotransduction of SV40 large T antigen. The iPSCs efficiently differentiated into HPV16-specific rejuvenated CTLs that demonstrated robust cytotoxicity against cervical cancer. The tumor-suppressive effect of rejuvenated CTLs was stronger and more persistent than that of original peripheral blood CTLs. These rejuvenated HPV16-specific CTLs provide a sustained tumor-suppressive effect even for epithelial cancers and constitute promising immunotherapy for cervical cancer.
Subject(s)
Cytotoxicity, Immunologic , Immunomodulation , Induced Pluripotent Stem Cells/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Uterine Cervical Neoplasms/immunology , Cell Differentiation/immunology , Female , Humans , Immunotherapy , Induced Pluripotent Stem Cells/cytology , Oncogene Proteins, Viral/immunology , Papillomavirus Infections/complications , Papillomavirus Infections/immunology , Papillomavirus Infections/virology , Repressor Proteins/immunology , T-Cell Antigen Receptor Specificity , T-Lymphocytes/cytology , T-Lymphocytes, Cytotoxic/immunology , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/therapy , Uterine Cervical Neoplasms/virologyABSTRACT
Functionally rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes (CTL) are expected to be a potent immunotherapy for tumors. When L-asparaginase-containing standard chemotherapy fails in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), no effective salvage therapy exists. The clinical course then is miserable. We demonstrate prolonged and robust eradication of ENKL in vivo by Epstein-Barr virus-specific iPSC-derived antigen-specific CTL, with iPSC-derived antigen-specific CTL persisting as central memory T cells in the mouse spleen for at least six months. The anti-tumor response is so strong that any concomitant effect of the programmed cell death 1 (PD-1) blockade is unclear. These results suggest that long-term persistent Epstein-Barr virus-specific iPSC-derived antigen-specific CTL contribute to a continuous anti-tumor effect and offer an effective salvage therapy for relapsed and refractory ENKL.