Graft-versus-leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene.
Mol Ther
; 21(2): 466-75, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-23299798
ABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T(CM)) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
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Leucemia
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Regulação Neoplásica da Expressão Gênica
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Efeito Enxerto vs Leucemia
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Genes Transgênicos Suicidas
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Antígenos HLA
Limite:
Adult
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Aged
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Aged80
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Animals
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article