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


METHODS
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.
Speetjens
Frank M
FM
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Kuppen
Peter J K
PJ
Welters
Marij J P
MJ
Essahsah
Farah
F
Voet van den Brink
Anne Marie E G
AM
Lantrua
M Graziella Kallenberg
MG
Valentijn
A Rob P M
AR
Oostendorp
Jaap
J
Fathers
Lorraine M
LM
Nijman
Hans W
HW
Drijfhout
Jan W
JW
van de Velde
Cornelis J H
CJ
Melief
Cornelis J M
CJ
van der Burg
Sjoerd H
SH
D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use
D019496:Cancer Vaccines; D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D022223:Vaccines, Subunit; C000609547:p53 synthetic long peptide vaccine