title: [(18)F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility.
abstract: Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75(+)-selected donor T cells (1.0-13 × 10(5))/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-((18)F)fluoro-3-hydroxymethyl-butyl]guanine ([(18)F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [(18)F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [(18)F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Linda G
authors: LG
authors: Eissenberg
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Michael P
authors: MP
authors: Rettig
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Julie K
authors: JK
authors: Ritchey
authors: Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Julie L
authors: JL
authors: Prior
authors: Department of Radiology Cyclotron Facility, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Sally W
authors: SW
authors: Schwarz
authors: Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA; Division of Nuclear Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Jennifer
authors: J
authors: Frye
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA; The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Brian S
authors: BS
authors: White
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Robert S
authors: RS
authors: Fulton
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Armin
authors: A
authors: Ghobadi
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Matthew L
authors: ML
authors: Cooper
authors: Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors: Daniel R
authors: DR
authors: Couriel
authors: Department of Biology, Culver-Stockton College, Canton, Missouri, USA.
authors: Muhammad Esa
authors: ME
authors: Seegulam
authors: Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Radiology Cyclotron Facility, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Cancer Systems Imaging and MD Anderson Cancer Center, Houston, Texas, USA.
authors: David
authors: D
authors: Piwnica-Worms
authors: Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA; Division of Nuclear Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Farrokh
authors: F
authors: Dehdashti
authors: Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility (IU VPF), Indianapolis, Indiana, USA.
authors: Kenneth
authors: K
authors: Cornetta
authors: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: jdipersi@dom.wustl.edu.
authors: John F
authors: JF
authors: DiPersio
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods*; D033581:Stem Cell Transplantation / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014184:Transplantation, Homologous / Q000379:methods*; D016896:Treatment Outcome
chemical_list: C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D018952:Antigens, CD34; D006147:Guanine; D013937:Thymidine Kinase; D015774:Ganciclovir