title: Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity.
abstract: Chimeric antigen receptor (CAR)-redirected cellular therapy is an attractive modality for cancer treatment. We hypothesized that allogeneic CAR-engineered CD45RA-negative T cells can control cancer and infection without the risk of graft-versus-host disease (GVHD). We used CD19(+) MLL-rearranged leukemia as prototype because it is an aggressive and generally drug-resistant malignancy. CD45RA(-) cells that were transduced with anti-CD19 CAR containing 4-1BB and CD3ζ signaling domains effectively lysed MLL-rearranged leukemia cell lines and primary blasts in vitro. In a disseminated leukemia mouse model, CAR(+)CD45RA(-) cells significantly reduced leukemia burdens and prolonged overall survival without GVHD. CAR(+) cells were sustainable in blood, and all the treated mice remained leukemia-free even after they were re-challenged with leukemia cells. Despite the transduction process, CD45RA(-) cells retained recall activity both in vitro and in vivo against human pathogens commonly found in cancer patients. In comparison with CD45RA(+) cells, CD45RA(-) cells showed less allogeneic activity in mixed leukocyte reactions and in mouse models. Thus, the use of CAR(+)CD45RA(-) cells can separate GVHD from graft-versus-malignancy effect and infection control. These cells should also be useful in nontransplant settings and may be administered as off-the-shelf third-party cells.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Suwannasaen
authors.affiliation: Vector Laboratory, Department of Experimental Hematology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Throm
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Application Laboratory, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Eldridge
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Houston
authors.affiliation: Vector Laboratory, Department of Experimental Hematology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Gray
authors.affiliation: 1] Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA [2] Department of Pediatrics, University of Tennessee, Memphis, TN, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.affiliation: 1] Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA [2] Department of Pediatrics, University of Tennessee, Memphis, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Leung
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D045744:Cell Line, Tumor; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007156:Immunologic Memory; D007938:Leukemia / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism; D011946:Receptors, Antigen / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D018941:Antigens, CD19; C497422:KMT2A protein, human; D011946:Receptors, Antigen; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D017493:Leukocyte Common Antigens