PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene …

W Koestner, M Hapke, J Herbst, C Klein… - Blood, The Journal …, 2011 - ashpublications.org
W Koestner, M Hapke, J Herbst, C Klein, K Welte, J Fruehauf, A Flatley, DA Vignali
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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