Ex vivo expanded telomerase-specific T cells are effective in an orthotopic mouse model for pancreatic adenocarcinoma.
Telomerase activity is over-expressed in nearly all pancreatic carcinomas, but not in chronic pancreatitis. Here, we investigated various protocols for expansion of telomerase-specific T cells for adoptive cell transfer and their use in a syngeneic pancreatic carcinoma mouse model. Telomerase-specific T cells were generated by stimulation of splenocytes from peptide-immunized donor mice with either interleukin (IL)-2, IL-15, artificial antigen-presenting cells, anti-signalling lymphocyte activation molecule (SLAM) microbeads or allogeneic dendritic cells in combination with a limited dilution assay. T cells were tested for antigen specificity in vitro and for anti-tumour activity in syngeneic mice with orthotopically implanted tumours pretreated with cyclophosphamide. The immune cells from recipients were immunophenotyped. During a period of 2 weeks, the expansion approach using IL-2 was very successful in generating a high number of telomerase-specific CD8(+) T cells without losing their function after adoptive cell transfer. Significantly slower tumour growth rate and less metastasis were observed after adoptively transferring telomerase specific CD8(+) T cells, expanded using IL-2. Further investigations showed that anti-tumour efficacy was associated with a significant shift from naive CD8(+) T cells to CD8(+) central memory T cells, as well as recruitment of a high number of dendritic cells. Remarkable amounts of telomerase-specific T cells were detectable in the tumour. Generation of telomerase-specific T cells is feasible, whereat IL-2-based protocols seemed to be most effective and efficient. Antigen-specific T cells showed significant cytotoxic activity in a syngeneic, orthotopic mouse model, whereas central memory T cells but not effector memory T cells appear to be of high importance.
Hassanin
H
H
Department of Surgery, University of Heidelberg, Heidelberg, Germany.
Serba
S
S
Schmidt
J
J
Märten
A
A
D000230:Adenocarcinoma / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019098:Telomerase / Q000276:immunology*; D014183:Transplantation, Heterologous
D000941:Antigens; D000939:Epitopes; D007376:Interleukin-2; D019098:Telomerase