title: Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia.
abstract: We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) models at the cost of severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T cells and mandates novel approaches for toxicity mitigation. We hypothesized that CAR T-cell depletion with optimal timing after AML eradication would preserve leukemia remission and allow subsequent hematopoietic stem cell transplantation. To test this hypothesis, we compared 3 CAR T-cell termination strategies: (1) transiently active anti-CD123 messenger RNA-electroporated CART (RNA-CART123); (2) T-cell ablation with alemtuzumab after treatment with lentivirally transduced anti-CD123-4-1BB-CD3ζ T cells (CART123); and (3) T-cell ablation with rituximab after treatment with CD20-coexpressing CART123 (CART123-CD20). All approaches led to rapid leukemia elimination in murine xenograft models of human AML. Subsequent antibody-mediated depletion of CART123 or CART123-CD20 did not impair leukemia remission. Time-course studies demonstrated that durable leukemia remission required CAR T-cell persistence for 4 weeks prior to ablation. Upon CAR T-cell termination, we further demonstrated successful hematopoietic engraftment with a normal human donor to model allogeneic stem cell rescue. Results from these studies will facilitate development of T-cell depletion strategies to augment the feasibility of CAR T-cell therapy for patients with AML.
authors.affiliation: Division of Oncology and.|Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Department of Pediatrics and.
authors.forename: Sarah K
authors.identifier: 0000-0003-1327-1662
authors.initials: SK
authors.lastname: Tasian
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN; and.
authors.forename: Saad S
authors.initials: SS
authors.lastname: Kenderian
authors.affiliation: Division of Oncology and.|Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: Marco
authors.initials: M
authors.lastname: Ruella
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Kozlowski
authors.affiliation: Division of Oncology and.|Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: April
authors.initials: A
authors.lastname: Schrank-Hacker
authors.affiliation: Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: Jennifer J D
authors.initials: JJD
authors.lastname: Morrissette
authors.affiliation: Abramson Cancer Center, and.|Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Department of Pathology and Laboratory Medicine.|Abramson Cancer Center, and.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Division of Oncology and.|Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Department of Pediatrics and.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Center for Cellular Immunotherapies, Translational Research Program, University of Pennsylvania School of Medicine, Philadelphia, PA.|Abramson Cancer Center, and.|Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Saar
authors.initials: S
authors.lastname: Gill
mesh_terms: D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016372:RNA, Antisense / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012074:Remission Induction; D000069283:Rituximab / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D016372:RNA, Antisense; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000074323:Alemtuzumab; D000069283:Rituximab