Research findings to be presented by The University of Texas MD Anderson Cancer Center at the American Society of Clinical Oncology’s 2014 Breast Cancer Symposium in San Francisco report that a new vaccine candidate for treating breast cancer, known as GP2, has been shown to inhibit the recurrence of the disease according to recent studies. The vaccines were shown to be particularly effective in treating high-risk patients using another immunotherapy drug in a combination therapy.
GP2 is a unique cancer vaccine — one of just a few in its class — and has already been proven both safe and effective in treating breast cancer by effectively reducing the recurrence rate of the disease by 57%. Most notably, breast cancer patients who have the highest level of HER2 overexpression, called HER2 +3, had 0% recurrence of cancer when given the vaccine just after receiving and completing a regimen of the monoclonal antibody immunotherapeutic trastuzumab (Herceptin). Given the fact that HER2 is found to be expressed in 75-80% of breast cancers, the new findings for GP2 are indeed promising.
A 2012 study published in the journal Chemotherapy Research and Practice entitled “The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy“ (Chemother Res Pract. 2012; 2012: 743193. Published online Dec 20, 2012. doi: 10.1155/2012/743193 PMCID: PMC3539433) by Zahi Mitri, Tina Constantine, and Ruth O’Regan of Emory University in Atlanta notes that Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in some 20-30% of breast cancer tumors and is associated with a more aggressive forms of the disease, higher recurrence rates, and increased mortality.
Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The Emory U. scientists observe that the effectiveness of Trastuzumab has been well validated in research as well as in clinical practice, and the addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer.
They report that the most clinically significant side effect of Trastuzumab is risk of cardiac myocyte injury, leading to development of congestive heart failure, and that emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive 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, M.D., Ph.D.. “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.”
Dr. Mittendorf is an Assistant Professor in the Department of Surgical Oncology at the University of Texas MD Anderson Cancer Center, where she focuses both her clinical and laboratory efforts on the study of breast cancer with a specific interest in breast cancer immunotherapy. She is the Principal Investigator on a number of clinical protocols including the phase III PRESENT (Prevention of Recurrence in Early-Stage, Node-.Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment) study, a multicenter phase II trial investigating the efficacy of two additional HER2-derived peptide vaccines and a single institution investigator-initiated phase I trial evaluating combination immunotherapy with vaccines and trastuzumab.
Work in Dr. Mittendorf’s laboratory is focused on identifying novel tumor antigens and investigating aspects of the tumor microenvironment that impact the response to vaccination. Specifically she is investigating cyclin E, a critical cell cycle regulator that is dysregulated in breast cancer as a target for vaccination as well as the impact of neutrophils present in the microenvironment as a link between innate immunity and adaptive immune responses to cancer. This work is supported by an R00 award from the National Cancer Institute, a Developmental Project award form the MD Anderson Cancer Center Breast SPORE grant and a Clinical Investigator Award from the Society of Surgical Oncology and Komen for the Cure Foundation.
Dr. Mittendorf has published extensively on breast cancer immunotherapy as well as on subjects related to the clinical management of breast cancer patients to include sentinel lymph node dissection, small volume metastatic disease, and outcomes following administration of neoadjuvant chemotherapy. Adjuvant therapies currently used for breast cancer are taken ongoing. “Otherwise, their effect to block cancer development is diminished, says Dr. Mittendorf. “In theory, once a response is generated with immunotherapy, we can expect a longer lasting therapeutic effect without repeated dosing.”
“The vaccine possibly offers advantages to today’s adjuvant therapies as well. Adjuvant therapies currently used for breast cancer are taken ongoing. Otherwise, their effect to block cancer development is diminished,” Dr. Mittendorf notes. “In theory, once a response is generated with immunotherapy, we can expect a longer lasting therapeutic effect without repeated dosing.”
The MD Anderson Center says the findings announced this month are result of a phase II randomized trial, which combined GP2, an immunotherapy formulated to stimulate CD8+ “killer T-cells,” together with the immune stimulant granulocyte/macrophage colony stimulating factor (GM-CSF). The trial, which included 190 patients with varying levels of HER2, featured 89 women who received GP2 together with the GM-CSF adjuvant, contrasted by a 91-patient control group, which received GM-CSF without Gp2. Of the entire study group, 8 patients reported early recurrence of the disease or developed a second malignancy, and were not able to complete the vaccine trial. The vaccine is administered by injecting it subcutaneously, with the initial series in the study consisting of an inoculation each month for 6 months. After this period, researchers administered four booster shot cycles, which were given every 6 months thereafter. After all vaccine injections were completed, the researchers monitored the patients for almost 3 years.
For all of the 190 patients who participated in the study, the disease-free survival (DFS) rate was observed to be 88% among the participants who were given the vaccine in conjunction with GM-CSF, and 81% in the control group that did not receive the vaccine along with GM-CSF, which represents a 37% reduction in recurrence. If patients who did not complete the vaccine series are excluded, the results are even higher, with a 94% DFS rate versus 85% who did not get GP2 a 57% risk reduction.
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 Dr. Mittendorf, trastuzumab may act like a primer for the vaccine, stimulating CD4+ T cells to release substances that fight cancer cells and initiating an antibody response. Thus, it may prepare the immune system, making the vaccine even more effective. MD Anderson is now testing this combination of immunotherapies in other clinical trials.
The GP2 study supports previous MD Anderson research on similar breast cancer vaccines, such as AE37, which showed the AE37 vaccine elicits a powerful immune response in women with varying levels of HER2 expression, has the ability to improve recurrence rates and is well tolerated in an adjuvant setting. Researchers found that patients who received the vaccination had an estimated recurrence rate of 10.3 percent, compared to 18 percent in the control group at a median follow up of 22 months, representing a 43 percent reduction in the risk of recurrence Another candidate, E75, known as NeuVax or nelipepimut-S, showed a 50% recurrence decrease in high-risk patients. Currently, NeuVax is being tested internationally in a phase III clinical trial.
“The vaccine educates the immune system to recognize HER2 as an invader,” commented Dr. Mittendorf in a MD Anderson release. “By introducing it into women who have had breast cancer, our goal is to instruct the immune system to immediately recognize any recurring cancer cells and orchestrate an attack.”
The AE37 peptide vaccine used in the 2012 study is a hybrid modified to increase its potency in generating an immune response specific to cancer cells expressing HER2. It consists of a fragment of the HER2 protein (AE36), a MHC Class II epitope, linked to an Ii-Key peptide. Together, they work to stimulate a robust CD4+ T cell response, prompting the components of the immune system to seek and destroy tumor cells.
To help T cells better recognize AE37, researchers also paired the vaccine with an immune stimulant known as granulocyte/macrophage colony stimulating factor (GM-CSF). The vaccine is injected under the skin similar to a tetanus shot. The initial series consists of inoculations given monthly for six months followed by four cycles of boosters every six months. MD Anderson currently has three different types of HER2-based peptide vaccines in various stages of testing and development. AE37 is the only one that targets CD4+ T cells.
“We believe many more patients will benefit in some way from immunotherapy,” says Dr. Mittendorf. “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.”
Other researchers contributing to the study include: Jennifer Litton, M.D.; James Murray, M.D., MPH; Guy Clifton, M.D. from MD Anderson; John Berry, M.D., Nathan Shumway, M.D., Timothy Vreeland, M.D., George Peoples, M.D., Erika Schneble, M.D., Julia Greene, M.D. and Alfred Trappey, M.D. from Brooke Army Medical Center; Sathibalan Ponniah, Ph.D. from Uniformed Services University of the Health Sciences; Alexandros Ardavanis, M.D., Michael Papamichail, M.D. and Sonia Perez, M.D. from Saint Savvas Cancer Hospital in Athens, Greece.
MD Anderson Cancer Center
Chemotherapy Research and Practice
MD Anderson Cancer Center