title: Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral vector-based vaccination in mice, but not man.
abstract: Mutations and aberrant expression of the p53 tumor suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the wild-type (wt) p53 protein and presented by major histocompatibility complex (MHC) molecules for T lymphocyte recognition are believed to serve as universal tumor-associated antigens for cancer immunotherapy. We studied the immunogeneicity of a recombinant replication-defective adenoviral vector encoding human full-length wt p53 (rAd/hup53) in human leukocyte antigen (HLA)-A2K(b)-transgenic (Tg) mice and man. The generation of p53 epitope-specific cytotoxic T lymphocytes (CTLs) in p53-proficient and p53-deficient A2K(b)-Tg mice was affected by self-tolerance and a selective inability of rAd/hup53 to induce p53.264-272 peptide-reactive effector cells. To extend this study into a pilot clinical trial, six advanced-stage cancer patients received sequential injections of rAd/hup53. The treatment was well tolerated. To date, no evidence for objective tumor responses was observed. An amplification of humoral and cellular anti-adenoviral immune responses was demonstrated in all patients following rAd/hup53 vaccination. However, p53-reactive antibodies and HLA-A*0201 (A2.1)-restricted CTLs specific for wt p53 epitopes were not generated. Tailoring p53-based cancer immunotherapy thus requires the interference with p53-specific self-tolerance and the induction of the entire repertoire of p53-reactive T lymphocytes.
authors.affiliation: Department of Hematology and Oncology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kuball
authors.forename: M
authors.initials: M
authors.lastname: Schuler
authors.forename: E
authors.initials: E
authors.lastname: Antunes Ferreira
authors.forename: W
authors.initials: W
authors.lastname: Herr
authors.forename: M
authors.initials: M
authors.lastname: Neumann
authors.forename: L
authors.initials: L
authors.lastname: Obenauer-Kutner
authors.forename: L
authors.initials: L
authors.lastname: Westreich
authors.forename: C
authors.initials: C
authors.lastname: Huber
authors.forename: T
authors.initials: T
authors.lastname: Wölfel
authors.forename: M
authors.initials: M
authors.lastname: Theobald
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010865:Pilot Projects; D017634:Self Tolerance; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016159:Tumor Suppressor Protein p53