[(18)F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

Mol Ther. 2015 Jun;23(6):1110-1122. doi: 10.1038/mt.2015.48. Epub 2015 Mar 25.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / genetics
  • Antigens, CD34 / immunology*
  • Antigens, CD34 / metabolism
  • Cell Line, Tumor
  • Feasibility Studies
  • Flow Cytometry
  • Ganciclovir / pharmacology
  • Graft vs Host Disease / immunology
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives
  • Herpesvirus 1, Human / genetics
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • NIH 3T3 Cells
  • Pilot Projects
  • Positron-Emission Tomography / methods*
  • Stem Cell Transplantation / methods*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Thymidine Kinase / genetics
  • Thymidine Kinase / metabolism
  • Transduction, Genetic*
  • Transplantation, Homologous / methods*
  • Treatment Outcome

Substances

  • 9-(4-fluoro-3-hydroxymethylbutyl)guanine
  • Antigens, CD34
  • Guanine
  • Thymidine Kinase
  • Ganciclovir