Vaccination with p53-peptide?pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study

Abstract

Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumour-associated epitopes. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as a basis for a broad-spectrum p53-targeting cancer vaccine. Our preclinical studies have shown that wild-type p53-derived HLA-A2-binding peptides are able to activate human T cells and that the generated effector T cells are cytotoxic to human HLA-A2+, p53+ tumour cells. In this phase I pilot study, the toxicity and efficacy of autologous dendritic cells (DCs) loaded with a cocktail of three wild-type and three modified p53 peptides are being analysed in six HLA-A2+ patients with progressive advanced breast cancer. Vaccinations were well tolerated and no toxicity was observed. Disease stabilisation was seen in two of six patients, one patient had a transient regression of a single lymph node and one had a mixed response. ELISpot analyses showed that the p53-peptide-loaded DCs were able to induce specific T-cell responses against modified and unmodified p53 peptides in three patients, including two of the patients with a possible clinical benefit from the treatment. In conclusion, the strategy for p53-DC vaccination seems safe and without toxicity. Furthermore, indications of both immunologic and clinical effect were found in heavily pretreated patients with advanced breast cancer. An independent clinical effect of repeated administration of DCs and IL-2 can not of course be excluded; further studies are necessary to answer these questions.

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

“…In several clinical trials using p53 peptides or a viral vector containing the wild-type p53 gene, generation of a specific immune response in some patients has been reported. However, no objective clinical responses have been observed (11,30,31). We hypothesized that the use of the most potent antigen-presenting cells, DCs, transduced with wildtype p53 might induce a more potent p53-specific immune response that would translate into a clinical response.…”

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial

“…A similar decrease in vaccine-induced p53-specific T-cell reactivity after multiple immunizations has also been observed in patients with breast cancer who were vaccinated with p53-peptide pulsed dendritic cells. 39 Formally, it cannot be excluded that the constant release of p53 peptides from the immunization sites may have resulted in the partial induction of hypo-responsiveness or apoptosis of p53-specific T-cells, but the isolation of poly-functional p53-specific T-cells from the immunization sites argues against this. In addition, an increase in regulatory T-cell activity due to repeated immunizations cannot be ruled out.…”

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…In addition, numerous clinical trials have been performed using different kinds of p53 vaccines including I) short and long peptide-based vaccines, II) dendritic cellbased vaccines, and III) recombinant replication-defective adenoviral vectors with human wild-type p53 (Kuball et al, 2002;Svane et al, 2004;Vermeij et al, 2011).…”