p53 immunotherapy in patients treated for metastasised colorectal cancer.

Introduction: Colorectal cancer is the second most frequent cancer in the Netherlands. Despite treatment 45% of all colorectal cancer patients die within 5 years. Efforts to improve survival with advanced colorectal cancer have had only limited success. P53 is a frequently overexpressed and mutated protein in colorectal cancer patients. This overexpression provides an immunological window for immunotherapy of colorectal cancer. It has been shown in animal models that vaccination for p53 specific immune response could eradicate tumours. In humans it has been shown that vaccination can induce a p53 immune response. Our approach is to vaccinate with peptides encoding the p53 protein.
Aim: To define safety and immunogenicity of a p53 specific vaccine in combination with a defined adjuvant. Secondary, to study the clinical response to vaccination.
Population: Patients will be selected from patients treated for colorectal metastases in the liver. Patients will be vaccinated at least three months after last treatment.
Method: A phase I/II study will be carried out. Five patients will be included in a phase I p53 based vaccine study. If in the first five patients no grade 3 or 4 toxicity occurs, we will automatically enter into a phase II study. The five patients of the phase I study will be analyzed in the same way as the next included patients. The phase II study ends if ten patients fully completed vaccination and follow-up.
Intervention: Patients will be vaccinated subcutaneously with a vaccine consisting of 10, overlapping long p53 peptides dissolved in the adjuvant Montanide ISA 51. Patients will be vaccinated two times with an interval of three weeks.
Safety: In a previous clinical study that we performed, in which patients were vaccinated with a canarypoxvirus with a human wildtype p53 inserted, no severe toxicity occurred. Also in a safety study with a HPV peptide vaccine (p 88/89-026) no serious side effects were detected.
Endpoints: Due to the length of the peptides both potential MHC class I and class II epitopes can be processed by antigen presenting cells, therefore both a p53 specific cellular and humoral response can be expected. In order to monitor the immune response, plasma and peripheral blood mononuclear cells will be isolated and tested from patients before and after p53 peptide vaccination. The reactions of the different assays is positive when one of the test is increased twice in the post-vaccination samples compared to the pre-vaccination sample. In all these assays the immune response against p53 will be compared before and after vaccination. To assess a clinical anti tumour response a CT scan will be made and CEA levels will be measured in blood samples before and after vaccination.

p53 mutation in colorectal cancer provides an immunological window for immune therapy.

Patients will be vaccinated subcutaneously with a vaccine consisting of 10, overlapping long p53 peptides dissolved in the adjuvant Montanide ISA 51. Patients will be vaccinated two times with an interval of three weeks.