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Updated: Aug 5, 2026
Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant
Published on: May 27, 2011
Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral vector-based vaccination in mice, but not
J Kuball1, M Schuler, E Antunes Ferreira
1Department of Hematology and Oncology, Johannes Gutenberg-University, Mainz, Germany.
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.
Insights
Cancer immunotherapy using wild-type p53 (wt p53) peptides faces challenges. A study found that while a p53-encoding adenoviral vector was safe in patients, it failed to generate crucial p53-specific T cells for tumor response.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mutations in the p53 tumor suppressor are common in human cancers.
- Wild-type p53 (wt p53) peptides presented by MHC molecules are potential cancer immunotherapy targets.
- Adenoviral vectors are used to deliver genetic material for therapeutic purposes.
Purpose of the Study:
- To evaluate the immunogenicity of a recombinant adenoviral vector encoding human wt p53 (rAd/hup53).
- To assess the potential of rAd/hup53 for cancer immunotherapy in preclinical models and a pilot clinical trial.
Main Methods:
- Studied immunogenicity in human leukocyte antigen (HLA)-A2K(b)-transgenic (Tg) mice.
- Administered rAd/hup53 to six advanced-stage cancer patients in a pilot clinical trial.
- Monitored for p53 epitope-specific cytotoxic T lymphocyte (CTL) generation and tumor responses.
Main Results:
- In mice, self-tolerance and vector-specific limitations hindered the generation of p53 epitope-specific CTLs.
- The rAd/hup53 treatment was well-tolerated in patients but did not yield objective tumor responses.
- Vaccination amplified anti-adenoviral immune responses but failed to generate p53-reactive antibodies or HLA-A*0201-restricted CTLs.
Conclusions:
- Current p53-based cancer immunotherapy strategies require overcoming p53-specific self-tolerance.
- Effective immunotherapy necessitates inducing a broader repertoire of p53-reactive T lymphocytes.
- Further research is needed to enhance the immunogenicity of p53-targeting cancer vaccines.
