title: Cytotoxic T cells reactive to an immunodominant leukemia-associated antigen can be specifically primed and expanded by combining a specific priming step with nonspecific large-scale expansion.
abstract: Identification of dominant leukemia-associated neoantigens and favoring specific priming and subsequent expansion of T cells reactive to these antigens might harbor therapeutic potential. Here, a new strategy combines a specific T-cell activation step using tumor lysate-pulsed bone marrow-derived dendritic cells with a nonspecific large-scale expansion method. The leukemia cell line C1498 transduced with a potentially immunodominant antigen (ovalbumin) was used to track expansion and functionality of antigen-specific cytotoxic T cell (CTL), both in vitro and in vivo. Three times more leukemia-specific CTL could be generated when compared with the respective controls. CTL generated after increasing the antigen-specific T-cell precursor frequency in vitro cured up to 80% of mice bearing leukemia with the respective antigen (P < 0.005, as compared with controls). Alternatively, the yield of CTL reactive to a immunodominant neoantigen increased by factor 2 to 6 when T-cell donors were immunized with dendritic cell presenting the respective antigen. However, increasing the leukemia-reactive precursor frequency to a clinically exploitable level will be the key for the design of successful T-cell therapy trials.
authors.affiliation: Transplantationsforschungszentrum, Department of Pediatric Hematology/Oncology Medizinische Hochschule Hannover, Germany.
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.forename: Matthias
authors.initials: M
authors.lastname: Wolenski
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sauer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004527:Egg Proteins / Q000235:genetics / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods; D007378:Interleukins / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D004527:Egg Proteins; D016056:Immunodominant Epitopes; D007378:Interleukins; D008562:Membrane Glycoproteins; C110366:OVA-8; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C028388:thymus-leukemia antigens; D010047:Ovalbumin