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.
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.
Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Wolfgang
W
Koestner
Martin
M
Hapke
Jessica
J
Herbst
Christoph
C
Klein
Karl
K
Welte
Joerg
J
Fruehauf
Andrew
A
Flatley
Dario A
DA
Vignali
Matthias
M
Hardtke-Wolenski
Elmar
E
Jaeckel
Bruce R
BR
Blazar
Martin G
MG
Sauer
D019264:Adoptive Transfer / Q000379:methods; D000595:Amino Acid Sequence; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007942:Leukemia, Experimental / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins