PMID- 12080377
OWN - NLM
STAT- MEDLINE
DCOM- 20020809
LR  - 20121115
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 9
IP  - 13
DP  - 2002 Jul
TI  - Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral 
      vector-based vaccination in mice, but not man.
PG  - 833-43
AB  - 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.
FAU - Kuball, J
AU  - Kuball J
AD  - Department of Hematology and Oncology, Johannes Gutenberg-University, Mainz, 
      Germany.
FAU - Schuler, M
AU  - Schuler M
FAU - Antunes Ferreira, E
AU  - Antunes Ferreira E
FAU - Herr, W
AU  - Herr W
FAU - Neumann, M
AU  - Neumann M
FAU - Obenauer-Kutner, L
AU  - Obenauer-Kutner L
FAU - Westreich, L
AU  - Westreich L
FAU - Huber, C
AU  - Huber C
FAU - Wolfel, T
AU  - Wolfel T
FAU - Theobald, M
AU  - Theobald M
LA  - eng
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Cancer Vaccines)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Adenoviridae/genetics/immunology
MH  - Animals
MH  - *Cancer Vaccines
MH  - Epitopes, T-Lymphocyte
MH  - *Genes, p53
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/administration & dosage
MH  - HLA-A2 Antigen/genetics
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplasms/immunology/*therapy
MH  - Pilot Projects
MH  - Self Tolerance
MH  - Species Specificity
MH  - T-Lymphocytes, Cytotoxic/*immunology
MH  - Treatment Failure
MH  - Tumor Suppressor Protein p53/*immunology
EDAT- 2002/06/25 10:00
MHDA- 2002/08/10 10:01
CRDT- 2002/06/25 10:00
PHST- 2001/11/02 00:00 [received]
PHST- 2002/02/22 00:00 [accepted]
PHST- 2002/06/25 10:00 [pubmed]
PHST- 2002/08/10 10:01 [medline]
PHST- 2002/06/25 10:00 [entrez]
AID - 10.1038/sj.gt.3301709 [doi]
PST - ppublish
SO  - Gene Ther. 2002 Jul;9(13):833-43. doi: 10.1038/sj.gt.3301709.