title: Successful elimination of large established tumors and avoidance of antigen-loss variants by aggressive adoptive T cell immunotherapy.
abstract: Utilization of ex vivo-expanded epitope-specific cytotoxic T lymphocytes has become a clinical standard in the adoptive immunotherapy of tumors. One of the obstacles faced by T cell-based immunotherapy is the development of tumor immune-escape variants. Using our previously reported CMS5 tumor/DUC18 CD8(+) TCR transgenic system, we sought to investigate whether large established tumors can be successfully eliminated before the development of escape variants. Using BALB/c mice that were s.c. transplanted with two tumors that had been growing for 8 days (double 8-day tumors), we assessed the in vivo anti-tumor activity of in vitro peptide-stimulated DUC18 T cells. A single infusion of activated DUC18 T cells showed a modest effect against the double 8-day tumors, whereas two and three administrations led to regression of both tumors within 10 days. However, in some mice, the tumors re-grew approximately 10 days after the regression. We found these tumors to be antigen-loss variants. These relapsed tumor cells progressively grew in DUC18 transgenic mice and did not express tERK-specific message. When four doses of activated DUC18 T cells were infused, the double 8-day tumors were successfully eliminated and the tumors did not grow out in any mice. Our results demonstrate that mono-specific CD8(+) T cells can effectively eliminate large established tumors before the development of antigen-loss variants when a high number of T cells is rapidly administered.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Matsui
authors.forename: Leigh A
authors.initials: LA
authors.lastname: O'Mara
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
mesh_terms: D000818:Animals; D000940:Antigenic Variation; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D014644:Genetic Variation; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; C482298:tERK-I peptide