Over the last decades, researchers have developed many new adjuvant and neoadjuvant treatment options for women with breast cancer. But because breast cancer is a complex disease not every patients benefits equally from the available treatment options. What's more, despite having no evidence of disease following surgery and chemotherapy/radiation, approximately 25% of resectable node-positive breast cancer patients will still relapse within three years. Increased presence of Circulating Tumor Cells or CTCs indicate decreased Disease Free Survival or DFS and Overall Survival or OS. This suggests the existence of a dormancy of isolated micrometastases, which over time, lead to recurrence. New treatment options, including therapeutic vaccines, may help treatment results.
These vaccines, made from peptides, stimulate the patients' immune system and may help the body build an effective immune response which is capable to kill tumor cells that express HER2/neu. One of these new threapeutic breast cancer vaccine candidate, GP2, provides further evidence of the potential of immunotherapy in preventing disease recurrence.
This is especially the case for high-risk patients when the vaccine is combined with a powerful immunotherapy drug. These findings are being presented by researchers from The University of Texas MD Anderson Cancer Center at the 2014 American Society of Clinical Oncology's (ASCO) Breast Cancer Symposium being held September 4 - 6, 2014 in San Francisco, California.
...we are investigating ways to prevent cancer recurrence by stimulating the immune system to treat cancer...
One of only a few vaccines of its kind in development, GP2 has been shown to be safe and effective for breast cancer patients. The trial vaccine reduces recurrence rates by 57%. Furthermore, women with the highest overexpression of HER2, which is also known as HER2 +3, had no cancer recurrences when they were administered the vaccine after completing trastuzumab (Herceptin®; Genentech/Roche), a type of immunotherapy drug known as a monoclonal antibody. HER2 is an oncoprotein that promotes tumor growth and is expressed to some extent in 75-80% of breast cancers.
"This is an important and different avenue in immunotherapy research, in that we are investigating ways to prevent cancer recurrence by stimulating the immune system to treat cancer," says principal investigator Elizabeth Mittendorf, MD., PhD., associate professor of Surgical Oncology. "The ultimate goal is to develop a preventative tool that will minimize the risk of recurrence in women who have already had breast cancer and for whom standard therapies have failed."
GP2 is a peptide vaccines which is made by taking a small amino acid sequence or peptide from a tumor-associated antigen - the HER2 oncoprotein, which promotes tumor growth. The GP2 peptide is 9 amino acids long and binds to MHC class I molecules to stimulate CD8+ T cells, which are commonly known as "killer" or "toxic" T cells.
After taking the peptide from the antigen, the GP2 vaccine is paired with an immunoadjuvant known as granulocyte-macrophage colony-stimulating factor or GM-CSF to help stimulate an immune response.
The findings are the result of a phase II randomized trial. The trial included 190 patients with varying levels of HER2. A total 89 women received the GP2 vaccine with a GM-CSF adjuvant and a control group of 91 patients received GM-CSF alone. Eight patients experienced early recurrence or developed a second malignancy and did not complete the vaccine trial. The vaccine is injected subcutaneously and the initial series consisted of monthly inoculations for six months, followed by four cycles of booster shots administered every six months thereafter. The patients were monitored for nearly three years.
For all 190 patients, including those who did not complete the trial, the disease-free survival or DFS rate was 88% among those who received the vaccine and 81% in the control group – representing a 37% reduction in recurrence. Excluding the patients who did not complete the vaccine series, the results are higher – 94% DFS rate versus 85% who did not get GP2 – a 57% risk reduction.
Standard of care
Women with HER2 +3 who were administered trastuzumab as part of the standard of care prior to receiving the vaccine experienced no cases of cancer recurrence. According to Mittendorf, trastuzumab may act like a primer for the vaccine. Trastuzumab stimulates CD4+ T cells to release substances that fight cancer cells and initiates an antibody response. Thus, it may prepare the immune system, making the vaccine even more effective.
Researchers at MD Anderson Cancer Center are now testing this combination of immunotherapies in other clinical trials. The results of the GP2 study supports previous research on similar breast cancer vaccines, including a vaccine called E75 or nelipepimut-S (NeuVax™; Galena Biopharma, Inc.) which showed a 50% recurrence decrease in high-risk patients. Currently, nelipepimut-S is being tested internationally in a phase III clinical trial. This 9-amino-acid HER2-derived peptide vaccines binds with major histocompatibility complex or MHC class I molecules and, just as GP2, stimulate CD8+ T cells. However, because this vaccine is an MHC class I peptide, the vaccine works only in patients whose cells are positive for human leukocyte antigen (HLA)-A2 or HLA-A3.
Following binding to HLA-A2 or HLA-A3 on antigen presenting cells or APC to elicit a robust, specific and durable, CD8+ Cytotoxic T Lymphocyte or CTL response follows. Activated specific CTLs recognize, neutralize and destroy, through a process of cell lysis, HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci, limiting disease recurrence.
Another candidate, AE37, which is being developed in collaboration with Generex Biotechnology Corporation's subsidiary Antigen Express, Inc., has shown a significant immune response and improved recurrence rates in triple-negative breast cancer patients. However, in contrast to the previous two candidates, GP2 and E75, the AE37 peptide is longer, binds to MHC class II molecules and stimulates CD4+ T cells, thereby eliciting a more robust immune response. Although MHC class II peptides can generally be HLA-restricted, AE37 is a so-called promiscuous peptide which means that blood cells of almost any HLA type can present it. Furthermore, the AE37 peptide is paired with the Ii-Key protein, which helps enhances the presentation of the peptide to the immune system.
Benefiting from immunotherapy
"We believe many more patients will benefit in some way from immunotherapy," Mittendorf explained. "The challenge will be identifying the right immunotherapeutic approach for each individual patient. When doctors are able to do that, cancer therapy, and immunotherapy specifically, will follow a more personalized approach."
For more information
 Schneble EJ, Perez SA, Murray JL, Berry JS, Trappey AF, Vreeland TJ, Hale DF, Greene JM, et al. Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients. 2014 Breast Cancer Symposium. Abstract Number: 134. J Clin Oncol 32, 2014 (suppl 26; abstr 134)
Photo: Elizabeth Mittendorf, MD, PhD, University of Texas M. D. Anderson Cancer Center. Photo Courtesy: MD Anderson Cancer Center.
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