title: Results of the first phase I/II clinical vaccination trial with direct injection of mRNA.
abstract: Vaccination against tumor antigens has been shown to be a safe and efficacious prophylactic and therapeutic antitumor treatment in many animal models. Clinical studies in humans indicate that specific immunotherapy can also result in clinical benefits. The active pharmaceutical ingredient in such vaccines can be DNA, RNA, protein, or peptide and can be administered naked, encapsulated, or after delivery in vitro into cells that are then adoptively transferred. One of the easiest, most versatile and theoretically safest technologies relies on the direct injection of naked messenger RNA (mRNA) that code for tumor antigens. We and others have shown in mice that intradermal application of naked mRNA results in protein expression and the development of an immune response. We used this protocol to vaccinate 15 melanoma patients. For each patient a growing metastasis was removed, total RNA was extracted, reverse-transcribed, amplified, and cloned. Libraries of cDNA were transcribed to produce unlimited amounts of copy mRNA. Autologous preparations were applied intradermally in combination with granulocyte macrophage colony-stimulating factor as adjuvant. We demonstrate here that such treatment is feasible and safe (phase 1 criteria). Furthermore, an increase in antitumor humoral immune response was seen in some patients. However, a demonstration of clinical effectiveness of direct injection of copy mRNA for antitumor immunotherapy was not shown in this study and must be evaluated in subsequent trials.
authors.affiliation: Department of Dermatology, Institute for Cell Biology, University of Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Carralot
authors.forename: Anne
authors.initials: A
authors.lastname: Reese
authors.forename: Birgit
authors.initials: B
authors.lastname: Scheel
authors.forename: Thomas Kurt
authors.initials: TK
authors.lastname: Eigentler
authors.forename: Ingmar
authors.initials: I
authors.lastname: Hoerr
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Steve
authors.initials: S
authors.lastname: Pascolo
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D015166:Monitoring, Immunologic / Q000379:methods; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D012333:RNA, Messenger; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor