PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells.
Blood
; 117(3): 1030-41, 2011 Jan 20.
Article
en En
| MEDLINE
| ID: mdl-21063028
ABSTRACT
Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR) genes is an attractive strategy to direct autologous T-cell immunity against tumor-associated antigens. However, clinical effectiveness has been hampered by limited in vivo persistence. We investigated whether the use of major histocompatibility complex-mismatched T cells would prolong the in vivo persistence of tumor-reactive TCR gene expressing T cells by continuous antigen-driven proliferation via the endogenous potentially alloreactive receptor. Donor-derived CD8(+) T cells engineered to express a TCR against a leukemia-associated antigen mediated strong graft-versus-leukemia (GVL) effects with reduced graft-versus-host disease (GVHD) severity when given early after transplantation. AT later after transplantation resulted in a complete loss of GVL. Loss of function was associated with reduced expansion of TCR-transduced T cells as assessed by CDR3 spectratyping analysis and PD-1 up-regulation on T cells in leukemia-bearing recipients. PD-L1 blockade in allogeneic transplant recipients largely restored the GVL efficacy without triggering GVHD, whereas no significant antileukemia effects of PD-L1 blockade were observed in syngeneic controls. These data suggest a clinical approach in which the AT of gene-modified allogeneic T cells early after transplantation can provide a potent GVL effect without GVHD, whereas later AT is effective only with concurrent PD-L1 blockade.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
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Glicoproteínas de Membrana
/
Antígeno B7-1
/
Linfocitos T CD8-positivos
/
Efecto Injerto vs Leucemia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Blood
Año:
2011
Tipo del documento:
Article
País de afiliación:
Alemania