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-γ 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-γ 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.
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Speetjens and co-workers reported that a synthetic peptide vaccine comprising 10 overlapping peptides derived from wtp53 regions rarely mutated effectively elicited a T cell response predominated by CD4+ T cells in metastatic colorectal cancer, with mild adverse events.
“In 2009, Speetjens and co-workers reported that a synthetic peptide vaccine, compound (252), comprising 10 overlapping peptides, with a sequence derived from regions of the wtp53 protein that are rarely mutated in cancer, effectively elicited a T cell response predominated by CD4+ T cells in metastatic colorectal cancer, with mild adverse events reported.589”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [589]
Clinical trials of peptide vaccines have shown mixed results even though the overall trend was positive.
“However, clinical trials have shown mixed results even though the overall trend was positive [155,156].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [156]
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- Authors
- Speetjens, F. M., Kuppen, P. J. K., Welters, M. J. P., Essahsah, F., Voet van den Brink, A. M. E. G., Lantrua, M. G. K., Valentijn, A. R. P. M., Oostendorp, J., Fathers, L. M., Nijman, H. W., Drijfhout, J. W., van de Velde, C. J. H., Melief, C. J. M., & van der Burg, S. H.
- Affiliations
- Leiden University (NL)
- ISA Pharmaceuticals (Netherlands) (NL)
- 1Surgery, Departments of
- University Medical Center Groningen (NL)
- 4Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands;
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2009-02-01
- Volume
- 15
- Issue
- 3
- Pages
- 1086-1095
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2132108367
- Cited by
- 185
- References
- 51
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 13 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 10 · 2018: 12 · 2017: 4 · 2016: 8 · 2015: 14 · 2014: 13 · 2013: 17 · 2012: 14
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- p53, metastatic colorectal cancer, CD4+ T cells, T cell polarization, Th1/Th2 cytokines, vaccine safety, cancer immunotherapy
- MeSH terms
- Aged, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, T-Lymphocytes, Cytotoxic, Colorectal Neoplasms, CD4-Positive T-Lymphocytes, Tumor Suppressor Protein p53, Cytokines, Cancer Vaccines, Vaccines, Subunit
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