title: HSV-sr39TK positron emission tomography and suicide gene elimination of human hematopoietic stem cells and their progeny in humanized mice.
abstract: Engineering immunity against cancer by the adoptive transfer of hematopoietic stem cells (HSC) modified to express antigen-specific T-cell receptors (TCR) or chimeric antigen receptors generates a continual supply of effector T cells, potentially providing superior anticancer efficacy compared with the infusion of terminally differentiated T cells. Here, we demonstrate the in vivo generation of functional effector T cells from CD34-enriched human peripheral blood stem cells modified with a lentiviral vector designed for clinical use encoding a TCR recognizing the cancer/testes antigen NY-ESO-1, coexpressing the PET/suicide gene sr39TK. Ex vivo analysis of T cells showed antigen- and HLA-restricted effector function against melanoma. Robust engraftment of gene-modified human cells was demonstrated with PET reporter imaging in hematopoietic niches such as femurs, humeri, vertebrae, and the thymus. Safety was demonstrated by the in vivo ablation of PET signal, NY-ESO-1-TCR-bearing cells, and integrated lentiviral vector genomes upon treatment with ganciclovir, but not with vehicle control. Our study provides support for the efficacy and safety of gene-modified HSCs as a therapeutic modality for engineered cancer immunotherapy. Cancer Res; 74(18); 5173-83. ©2014 AACR.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Gschweng
authors.affiliation: Department of Medical and Molecular Pharmacology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: McCracken
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Kaufman
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ho
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
authors.forename: Roger P
authors.initials: RP
authors.lastname: Hollis
authors.affiliation: Department of Medicine Statistics Core, University of Los Angeles, Los Angeles, Los Angeles, California.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Saini
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.affiliation: Department of Medical and Molecular Pharmacology, University of California, Los Angeles, Los Angeles, California. Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California. Department of Medical and Molecular Pharmacology, University of California, Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California. Department of Pediatrics, Division of Hematology/Oncology, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, California. dkohn@mednet.ucla.edu.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000097:blood / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000000981:diagnostic imaging / Q000276:immunology / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell