期刊
HUMAN GENE THERAPY
卷 19, 期 9, 页码 937-950出版社
MARY ANN LIEBERT INC
DOI: 10.1089/hum.2007.156
关键词
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资金
- Programme Hospitalier de Recherche Clinique [PHRC 950898, RC39]
- Ligue Nationale contre le Cancer
- Comites du Doubs and Jura
- Fondation Transplantation [ET-050318]
- Association Francaise contre la Myopathie
- Ministere de I'Enseignement Superieur et de la Recherche (Centre Reseau de Developpement des Therapies Geniques [CRTG])
- Association pour la Recherche sur le Cancer [4350]
- Genetic Therapy, Inc.
- Novartis
- European Community [CT97-2074]
- Ligue contre le Cancer
- Comite du Doubs
- J Lira
Administration of herpes simplex thymidine kinase (HSV-tk)-expressing, gene-modified T cells (GMCs) with T cell-depleted bone marrow transplantation (TCD-BMT) can allow modulation of posttransplantation alloreactivitv. Twelve patients received 2 X 10(5) to 2 X 10(6) CD3(+) donor GMCs per kilogram with HLA-identical sibling TCD-BMT. Despite extensive T cell depletion of bone marrow, ail intensive conditioning regimen, and immunosuppressive graft-versus-host disease (GvHD) prophylaxis, infusion at the time of TCD-BMT of this low number of GMCs Sufficed to induce a rapid GMC-specific immune response, as detected by interferon-y enzyme-linked immunospot assay in six of eight patients, preferentially targeting HSV-tk. Maximal responses were reached early (median time, 49 [135-68] days post-BMT), with a subsequent rapid and significant decrease in five of six evaluable patients. Immune responses were negatively correlated with the maximal circulating GMC Counts. However, such immune response did not result in the elimination of circulating GMCs and was not associated with measurable ex vivo cytotoxic activity against GMCs. Furthermore, alloreactive GMCs still could induce GCV-sensitive GvHD in one patient despite an ongoing immune response. Overall, infusion of HSV-tk-expressing GMCs at the time of BMT results in an early immune response. Such immune response may be altered and may not prevent persistent GCV-sensitive alloreactivity.
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