Primary allogeneic T-cell responses against mantle cell lymphoma antigen-presenting cells for adoptive immunotherapy after stem cell transplantation.
OBJECTIVE
In patients treated with allogeneic stem cell transplantation for advanced mantle cell lymphoma (MCL), complete sustained remissions have been observed illustrating susceptibility of MCL cells to a graft-versus-lymphoma effect. To potentiate this graft-versus-lymphoma effect, adoptive transfer of in vitro selected MCL-specific CTL can be an attractive approach. The lack of expression of costimulatory molecules on MCL cells hampers the generation of MCL-reactive T-cell responses. The purpose of this study was to modify MCL cells into antigen-presenting cells (APC) and to use these MCL-APCs to induce allogeneic MCL-reactive T-cell responses.


METHODS
Interleukin (IL)-4, IL-10, CpG, and CD40 activation were tested for their capacity to up-regulate costimulatory molecules on MCL cells. Primary MCL cells or the modified MCL-APCs were then used to evaluate the induction of MCL-reactive T-cell responses in HLA-matched donors.


RESULTS
Ligation of CD40 on MCL cells was essential to up-regulate costimulatory molecules and to induce production of high amounts of IL-12. In contrast to primary MCL cells, MCL-APC cells as stimulators were capable of inducing CD8+ CTL lines from HLA class I-matched donors. High numbers of CTL clones could be generated capable of efficiently killing the primary MCL cells and MCL-APC but not donor-specific targets.


CONCLUSIONS
These results show the feasibility to generate primary allogeneic T-cell responses against MCL-APC, and may provide new immunotherapeutic tools to further exploit the graft-versus-lymphoma effect following allogeneic stem cell transplantation in patients with MCL.
Hoogendoorn
Mels
M
Department of Hematology, Laboratory of Experimental Hematology, Leiden University Medical Center, Leiden, The Netherlands. M.Hoogendoorn@lumc.nl
Olde Wolbers
Judith
J
Smit
Willem M
WM
Schaafsma
M Ronald
MR
Jedema
Inge
I
Barge
Renee M Y
RM
Willemze
Roel
R
Falkenburg
J H Frederik
JH
D000328:Adult; D000368:Aged; D000938:Antigen-Presenting Cells / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D020350:Graft vs Tumor Effect; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D016207:Cytokines