title: A polyvalent cellular vaccine induces T-cell responses against specific self-antigens overexpressed in chronic lymphocytic B-cell leukemia.
abstract: B cell-derived chronic lymphocytic leukemia (CLL) is an incurable disease that requires innovative therapeutic regimens. Experimental approaches of immunotherapy aiming at induction of systemic T-cell responses have been developed. Trioma cells provide a potent vaccine derived from malignant B cells that allows multiple antigens (Ags) from the parental tumor to be ingested by Ag-presenting cells. Like other strategies using modified whole tumor cells, this approach induces polyvalent responses. Using trioma cell-pulsed dendritic cells (DCs) for T-cell activation in vitro, we asked whether specific Ags overexpressed by CLL can be identified as target structures of such responses and what is the nature of these Ags. Expression levels of several genes in CLL samples were quantitated by reverse transcriptase-polymerase chain reaction. T lymphocytes were polyvalently stimulated by trioma-pulsed DCs and specificities were tested by determining cytokine secretion in the presence of target cells transfected with RNA coding for those Ags that were found to be overexpressed. We demonstrate that DCs pulsed with the modified tumor cells efficiently activate T lymphocytes against CLL and that overexpressed Ags related to leukemogenesis, such as BCL-2, MDM2, and ETV5, serve as targets for those T cells. Immune escape by Ag loss or mutation is less likely to occur if immunity is directed against altered self-proteins that are involved in malignant transformation. Therefore, vaccines based on modified tumor cells such as triomas hold promise for immunotherapy of CLL and other malignancies. Polyvalent vaccines originally designed as individualized therapeutics may be more broadly applicable, at least in patients showing similar Ag patterns.
authors.affiliation: Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Institut für Molekulare Immunologie München, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Kronenberger
authors.forename: Elfriede
authors.initials: E
authors.lastname: Nössner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Frankenberger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wahl
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Ralph
authors.initials: R
authors.lastname: Mocikat
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2