Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer.

Abstract

PURPOSE:

The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic colorectal cancer.

EXPERIMENTAL DESIGN:

Ten patients were vaccinated twice with a set of 10 overlapping p53-SLP in a phase I/II trial. Both the safety and the breadth, magnitude, and polarization of vaccine-induced p53-specific T cells was evaluated in blood samples drawn before and after vaccination by IFN-gamma enzyme-linked immunospot, proliferation, cytokine secretion, and multiparameter flow cytometry. The migratory capacity of p53-specific T cells was evaluated by assessing their presence in a biopsy of the second vaccination site.

RESULTS:

Toxicity was limited to grade 1/2, mostly at the vaccination site. p53-specific T-cell responses were induced in 9 of 10 colorectal cancer patients as measured by IFN-gamma enzyme-linked immunospot, proliferation, and cytokine bead array. In 6 of 9 tested patients, p53-specific T-cell reactivity persisted at least 6 months. Furthermore, p53-specific T cells isolated from the vaccination site were characterized as CD4+ T cells producing both T-helper types 1 and 2 cytokines on stimulation with p53 peptide and p53 protein. Multiparameter flow cytometry revealed that only a minor population of the p53-specific CD4+ T cells was optimally polarized.

CONCLUSIONS:

The p53-SLP vaccine is safe and capable to induce p53-specific T-cell responses in patients treated for colorectal cancer. New trials should focus on improving the polarization of the p53-SLP vaccine-induced T-cell response.

• Authors: Frank M Speetjens, Peter J K Kuppen, Marij J P Welters, Farah Essahsah, Anne Marie E G Voet van den Brink, M Graziella Kallenberg Lantrua, A Rob P M Valentijn, Jaap Oostendorp, Lorraine M Fathers, Hans W Nijman, Jan W Drijfhout, Cornelis J H van de Velde, Cornelis J M Melief, Sjoerd H van der Burg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 3 Pg. 1086-95 (Feb 01 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19188184 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• Cytokines
• Tumor Suppressor Protein p53
• Vaccines, Subunit
• p53 synthetic long peptide vaccine

Topics

• Aged
• CD4-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (adverse effects, immunology, therapeutic use)
• Colorectal Neoplasms (immunology, pathology, therapy)
• Cytokines (biosynthesis)
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• T-Lymphocytes, Cytotoxic (immunology)
• Tumor Suppressor Protein p53 (adverse effects, immunology, therapeutic use)
• Vaccines, Subunit (adverse effects, immunology, therapeutic use)