title: CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia.
abstract: Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.
authors.affiliation: 1] Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Division of Hematology and Bone Marrow Transplantation, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Kenderian
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ruella
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Shestova
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Klichinsky
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Aikawa
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J J D
authors.initials: JJ
authors.lastname: Morrissette
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Scholler
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Song
authors.affiliation: 1] Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: June
authors.affiliation: 1] Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gill
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015153:Blotting, Western; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D063268:Sialic Acid Binding Ig-like Lectin 3