title: Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy.
abstract: Effective T-cell therapy against cancer is dependent on the formation of long-lived, stem cell-like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell-like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients and their ex vivo generation for additive treatment posttransplant. Early after allo-SCT, CD8+ stem cell memory T cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were not detectable, emphasizing the need for improved additive MiHA-specific T-cell therapy. Importantly, MiHA-specific CD8+ T cells with an early CCR7+CD62L+CD45RO+CD27+CD28+CD95+ memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt signaling during ex vivo priming and expansion. This resulted in a MiHA-specific CD8+ T-cell population containing a high proportion of stem cell-like T cells compared with terminal differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8+ T cells showed a superior expansion capacity in vitro and in immunodeficient mice and induced a superior antitumor effect in intrafemural multiple myeloma-bearing mice. These findings provide a rationale for clinical exploitation of ex vivo-generated Akt-inhibited MiHA-specific CD8+ T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients.
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Anniek B
authors.initials: AB
authors.lastname: van der Waart
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Noortje M P
authors.initials: NM
authors.lastname: van de Weem
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Cynthia S M
authors.initials: CS
authors.lastname: Kramer
authors.affiliation: Department of Hematology, Laboratory of Experimental Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.affiliation: Department of Hematology, Laboratory of Experimental Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.affiliation: Department of Hematology; Radboud university medical center, Nijmegen, The Netherlands; and.
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Schaap
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.affiliation: Experimental Transplantation and Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Willemijn
authors.initials: W
authors.lastname: Hobo
authors.affiliation: Department of Laboratory Medicine-Laboratory of Hematology; Radboud university medical center, Nijmegen, The Netherlands;
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D002478:Cells, Cultured; D003131:Combined Modality Therapy / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: C532657:1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one; D001562:Benzimidazoles; D015778:Minor Histocompatibility Antigens; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D051057:Proto-Oncogene Proteins c-akt