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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 467-474
Long-term in vivo survival of receptor-modified syngeneic T cells
in patients with human immunodeficiency virus infection
Robert E. Walker,
Christine M. Bechtel,
Ven Natarajan,
Michael Baseler,
Kristen M. Hege,
Julia A. Metcalf,
Randy Stevens,
Allison Hazen,
R. Michael Blaese,
Clara C. Chen,
Susan F. Leitman,
Jolie Palensky,
Janet Wittes,
Richard T. Davey Jr,
Judith Falloon,
Michael A. Polis,
Joseph A. Kovacs,
David F. Broad,
Bruce L. Levine,
Margo R. Roberts,
Henry Masur, and
H. Clifford Lane
From the Clinical and Molecular Retrovirology Section, Laboratory of
Immunoregulation, National Institute of Allergy and Infectious
Diseases, Clinical Gene Therapy Branch, National Human Genome Research
Institute, and the Departments of Nuclear Medicine, Transfusion
Medicine, and Critical Care Medicine, Clinical Center, National
Institutes of Health, Bethesda, MD; SAIC/Frederick, Frederick Cancer
Research and Development Center, Frederick, MD; Cell Genesys, Inc,
Foster City, CA; Statistics Collaborative, Washington, DC; and the
Leonard and Madlyn Abramson Family Cancer Research Institute at the
University of Pennsylvania Cancer Center, Philadelphia, PA.
To study human immunodeficiency virus (HIV)-specific cellular
immunity in vivo, we transferred syngeneic lymphocytes after ex vivo
expansion and transduction with a chimeric receptor gene (CD4/CD3- )
between identical twins discordant for HIV infection. Single and
multiple infusions of 1010 genetically modified
CD8+ T cells resulted in peak fractions in the
circulation of approximately 104 to 105
modified cells/106 mononuclear cells at 24 to 48 hours,
followed by 2- to 3-log declines by 8 weeks. In an effort to provide
longer high-level persistence of the transferred cells and possibly
enhance anti-HIV activity, we administered a second series of infusions
in which both CD4+ and CD8+ T cells were
engineered to express the chimeric receptor and were costimulated ex
vivo with beads coated with anti-CD3 and anti-CD28. Sustained fractions
of approximately 103 to 104 modified
cells/106 total CD4+ or CD8+
cells persisted for at least 1 year. Assessment of in vivo trafficking of the transferred cells by lymphoid tissue biopsies revealed the
presence of modified cells in proportions equivalent to or below those
in the circulation. The cell infusions were well tolerated and were not
associated with substantive immunologic or virologic changes. Thus,
adoptive transfer of genetically modified HIV-antigen-specific T cells
was safe. Sustained survival in the circulation was achieved when
modified CD4+ and CD8+ T cells were infused
together after ex vivo costimulation, indicating the important role
played by antigen-specific CD4+ T cells in providing
"help" to cytotoxic effectors.
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