Abstract
MUC1, a tumor-associated antigen overexpressed in many carcinomas, represents a candidate of choice for cancer immunotherapy. Flagella-based MUC1 vaccines were tested in therapeutic setting in two aggressive breast cancer models, comprising the implantation of the 4T1-MUC1 cell line in either Balb/c, or Human MUC1 transgenic mice in which spontaneous metastases occurs. Recombinant flagella carrying only 7 amino acid of MUC1 elicited therapeutic activity, affecting both the growth of established growing tumors and the number of metastases. Higher therapeutic activity was achieved with an additional recombinant flagella designed with the SYFPEITHI algorithm. The vaccines triggered a Th1 response against MUC1 with no evident autoimmune response towards healthy MUC1-expressing tissues. Recombinant flagella carrying a 25-residue fragment of MUC1, induced the most effective response, as evidenced by a significant reduction of both the size and growth rate of the tumor as well as by the lower number of metastases, and expanding life span of vaccinated mice.
Highlights
In spite of pronounced improvements in cancer management over the last decade, traditional cancer treatments remain limited in their therapeutic capacity and are accompanied by adverse side effects
In order to validate the potential use of recombinant flagella as a mucin 1 (MUC1)-based cancer vaccine, we initially tested the therapeutic capacity of a recombinant vaccine denoted Fla-MUC1.7 carrying the 7 residues immunodominant epitope (APDTRPA) [3,4,5,6]
Twelve days post-immunization, the tumor growth was 3-fold lower as a result of the single administration of Fla-MUC1.7 compared to the growth monitored in control mice immunized either with a control recombinant vaccine denoted Fla-NRP or with PBS (p < 0.05) (Figure 1(a))
Summary
In spite of pronounced improvements in cancer management over the last decade, traditional cancer treatments remain limited in their therapeutic capacity and are accompanied by adverse side effects. Cancer vaccines, based on tumor associated-antigens, represent an attractive therapeutic strategy. They are aimed at inducing a specific immune response towards the tumor, they are usually not associated with toxic side effects and they can establish a long-term immune memory, which is critical in preventing tumor recurrence [1]. The tumor associated antigen mucin 1 (MUC1) is a high molecular weight transmembrane glycoprotein expressed on the apical surface of most of the glandular epithelial cells [2]. Its antigenicity is different in malignant and normal cells, which allows the immune system to distinguish between them [1]. The utilization of MUC1 in immunotherapeutic approaches for the development of either peptide, carbohydrate, DNA or dendritic cells-based vaccines, was reported. Promising results with such vaccines were achieved in animal models, but moving to the clinical arena, several trials using MUC1 based vaccines, employing different carriers and/or adjuvant, did not exhibit sufficient efficacy [5,6]
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