High immunogenic potential of p53 mRNA-transfected dendritic cells in patients with primary breast cancer

Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Copenhagen, 2730, Herlev, Denmark.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 03/2010; 125(2):395-406. DOI: 10.1007/s10549-010-0844-9
Source: PubMed


As pre-existent immunity might be a reflection of an emerging anticancer response, the demonstration of spontaneous T-cell responses against tumor associated antigens (TAAs) in cancer patients may be beneficial before clinical development of dendritic cell (DC)-based cancer vaccines, because it will help to identify likely responders to TAAs among patients who qualify and may benefit from this form of immune therapy. This study aimed to determine pre-existent T-cell reactivity against the tumor suppressor protein p53 in breast cancer patients (BCP) at the time point of primary diagnosis. After a short-term stimulation with autologous wt p53 mRNA-transfected DCs, IFN-γ enzyme-linked immunosorbent spot (ELISPOT) analysis revealed p53-reactive T cells in the peripheral blood of more than 40% (15 of 36) of the tested patients. Both CD4(+) and CD8(+) p53-specific T cells secreted IFN-γ after stimulation with p53-transfected DCs. Interestingly, more than 72% (13 of 18) of patients with high p53 (p53(high)) expression in tumors were able to mount a p53-specific IFN-γ T-cell response, in contrast to only 10% (1 of 10) of healthy donors and 11% (2 of 18) of patients with low or absent p53 (p53(low)) expression in tumors. Furthermore, significantly higher secretion of IL-2 was detected in peripheral blood mononuclear cells after stimulation with p53-transfected DCs from patients with p53(high) tumor expression compared to patients with p53(low) tumor expression, whereas secretion of IL-10 was predominant in the latter group. The high frequency of spontaneous wt p53-reactive T cells detected in the peripheral blood of primary BCP with accumulation of p53 in tumor provides a rationale to consider DCs transfected with mRNA encoding wt p53 for clinical investigation in these patients.

Download full-text


Available from: Eva Balslev,
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the TP53 gene are a feature of 50% of all reported cancer cases. In the other 50% of cases, the TP53 gene itself is not mutated but the p53 pathway is often partially inactivated. Cancer therapies that target specific mutant genes are proving to be highly active and trials assessing agents that exploit the p53 system are ongoing. Many trials are aimed at stratifying patients on the basis of TP53 status. In another approach, TP53 is delivered as a gene therapy; this is the only currently approved p53-based treatment. The p53 protein is overexpressed in many cancers and p53-based vaccines are undergoing trials. Processed cell-surface p53 is being exploited as a target for protein-drug conjugates, and small-molecule drugs that inhibit the activity of MDM2, the E3 ligase that regulates p53 levels, have been developed by several companies. The first MDM2 inhibitors are being trialed in both hematologic and solid malignancies. Finally, the first agent found to restore the active function of mutant TP53 has just entered the clinic. Here we discuss the basis of these trials and the future of p53-based therapy.
    Nature Reviews Clinical Oncology 10/2010; 8(1):25-37. DOI:10.1038/nrclinonc.2010.174 · 14.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation still require optimization. An alternative technique for providing antigens to DC consists of the direct fusion of dendritic cells with tumor cells. These resulting hybrid cells may express both major histocompatibility complex (MHC) class I and II molecules associated with tumor antigens and the appropriate co-stimulatory molecules required for T-cell activation. Initially tested in animal models, this approach has now been evaluated in clinical trials, although with limited success. We summarize and discuss the results from the animal studies and first clinical trials. We also present a new approach to inducing hybrid formation by expression of viral fusogenic membrane glycoproteins.
    Cytotherapy 08/2011; 13(7):774-785. DOI:10.3109/14653249.2011.553593 · 3.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The observation that dendritic cells (DCs) charged with tumor-associated antigens (TAAs) is a potent strategy to elicit protective immunity in tumor-bearings hosts has prompted extensive testing of DCs as cellular adjuvant in cancer vaccines. To improve the clinical development of DC-based cancer vaccines, it may be beneficial to analyze preexistent immunity against TAAs in cancer patients because it may be easier to expand a memory pool of T cells compared to generating new immunity. Recent research shows that engineering DCs to synthesize tumor epitopes endogenously by transfecting DCs with mRNA-encoding TAAs are particular effective in stimulating robust T-responses in vitro and in vivo. In this chapter, we describe the methodology to analyze for survivin-specific T cells in breast cancer patients using human DCs engineered with survivin mRNA.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 969:275-92. DOI:10.1007/978-1-62703-260-5_17 · 1.29 Impact Factor
Show more