Abstract
The overarching hypothesis we are testing is that the best therapeutic approach to cancer is to prevent it either by preventing development of precursor lesions in high-risk individuals or arresting their progression from early lesions to invasive cancer. In the history of medicine, the most effective disease prevention has been achieved through vaccination. There is now solid evidence that tumors are recognized by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Immune recognition and tumor elimination are mediated by the adaptive immune system and directed against specific tumor antigens.
We have explored the potential of one such antigen, MUC1, to be a good immunogen as well as a good target of anti-tumor immunity. The experiments have involved in vitro trials, animal models and Phase I and II clinical trials. All MUC1 vaccines tested by us and others have been “therapeutic,” administered to patients with late stage cancer and often after failing standard toxic therapies. In that setting there was very low immunogenicity and limited therapeutic efficacy. It is now clear that the immune system of a cancer patient is under the influence of multiple stress pathways, both tumor induced and host induced, which have a profound immunosuppressive effect, especially on the adaptive immune cells responsible for eliminating tumor cells.
We took advantage of the fact that MUC1 that is abnormally expressed on tumor cells is also abnormally expressed on precursor lesions that can progress to cancer. For example, MUC1 is a tumor antigen on colon tumors but also abnormally expressed on all different types of colonic polyps, precursors to colon cancer. We conducted a clinical trial testing a MUC1 vaccine in individuals diagnosed with villous colonic adenomas, the immediate precursor lesions for colon cancer. Our hypothesis was that the immune system of these individuals would not have experienced the stress pathways associated with the cancer microenvironment and thus would generate a good immune response to the vaccine, which could prevent adenoma recurrence or their progression to colon cancer.
We vaccinated 40 individuals with a 100aa-long MUC1 peptide combined with the TLR3 agonist adjuvant Poly-ICLC (HiltonolÒ). The vaccine was given at Day 0, week 2, week 10 and week 52 (1-year booster). 47% of individuals responded vigorously to the vaccine as measured by anti-MUC1 IgG. All responders had a vigorous memory response at 1 year. There was no toxicity of any kind.
We also focused our attention on the 53% who were non-responders. There was no correlation between response to the vaccine and age or race and only a slight correlation with gender. The surprise came when we examined the immunocompetence of these individuals by evaluating the state of CD4 and CD8 T cells and the presence or absence of Treg and MDSCs. Treg and MDSC have been found in increased numbers at the tumor site and in circulation of advanced cancer patients. They have not been reported in people with premalignant lesions. We found a highly statistically significant correlation between high percentages of MDSCs in the blood and non-responsiveness to the vaccine. We also found that, unlike in cancer, there was no increase in Treg in premalignancy. Furthermore, again unlike in cancer patients, once MDSCs are removed, the T cells function normally and have a normal effector phenotype rather than the phenotype of exhausted T cells.
We draw three important conclusions from this trial: 1) the MUC1 plus Poly-ICLC adjuvant is an immunogenic vaccine; 2) progressive premalignant disease can also create a “stressful” environment that can interfere with effective immunosurveillance. Cancer vaccines should be administered before MDSC expand or in combination with treatments that would control or eliminate MDSC function.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN08-04.
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