title: Adoptive Transfer of CD8+ T Cells Generated from Induced Pluripotent Stem Cells Triggers Regressions of Large Tumors Along with Immunological Memory.
abstract: Current approaches to adoptive T-cell therapy are limited by the difficulty of obtaining sufficient numbers of T cells against targeted antigens with useful in vivo characteristics. Theoretically, this limitation could be overcome by using induced pluripotent stem cells (iPSC) that could provide an unlimited source of autologous T cells. However, the therapeutic efficacy of iPSC-derived regenerated T cells remains to be demonstrated. Here, we report the first successful reprogramming of T-cell receptor (TCR) transgenic CD8(+) T cells into pluripotency. As part of the work, we established a syngeneic mouse model for evaluating in vitro and in vivo antitumor reactivity of regenerated T cells from iPSCs bearing a rearranged TCR of known antigen specificity. Stably TCR retained T-cell-derived iPSCs differentiated into CD4(+)CD8(+) T cells that expressed CD3 and the desired TCR in vitro Stimulation of iPSC-derived CD4(+)CD8(+) T cells with the cognate antigen in the presence of IL7 and IL15 followed by expansion with IL2, IL7, and IL15 generated large numbers of less-differentiated CD8(+) T cells with antigen-specific potent cytokine production and cytolytic capacity. Furthermore, adoptively transferred iPSC-derived CD8(+) T cells escaped immune rejection, mediated effective regression of large tumors, improved survival, and established antigen-specific immunological memory. Our findings illustrate the translational potential of iPSCs to provide an unlimited number of phenotypically defined, functional, and expandable autologous antigen-specific T cells with the characteristics needed to enable in vivo effectiveness. Cancer Res; 76(12); 3473-83. ©2016 AACR.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Saito
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York. Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York. fumito.ito@roswellpark.org.
authors.forename: Fumito
authors.initials: F
authors.lastname: Ito
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D005260:Female; D007156:Immunologic Memory; D057026:Induced Pluripotent Stem Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D016207:Cytokines