Posted May 1, 2014
Elizabeth Mittendorf, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
George Peoples, M.D., COL, U.S. Army, Brooke Army Medical Center
An ideal treatment for ending breast cancer would be one that triggers the body's own defense systems to kill tumor cells - for the rest of a person's life. Dr. Elizabeth Mittendorf and others are attempting to create just such a remedy with a vaccine that targets the HER2 protein in breast cancer. The vaccine, called NeuVax™, is currently being evaluated in a phase III clinical trial enrolling patients with low HER2-expressing tumors (scored as 1+ or 2+ by immunohistochemistry). If the vaccine shows benefit to patients, NeuVax™ could be used to routinely treat these patients within the next 3 to 5 years. Additional work being done by Dr. Mittendorf and her collaborator COL (Dr.) George Peoples suggests that when used in combination with trastuzumab in patients with the highest level of HER2 (immunohistochemistry 3+; = HER2-positive) NeuVax™ may also be effective. A clinical trial is being designed to address this patient population.
NeuVax™ has arrived at this point after many years of work - work that began with a productive collaboration at Walter Reed National Military Medical Center. As the retired Air Force Major recounts:
"I served on active duty in the U.S. Air Force from 2001-2005. I was stationed at Andrews Air Force Base but due to deployments by my colleagues in the Army, spent a lot of time at the Walter Reed Army Medical Center, where I met COL (Dr.) George Peoples and began collaborating with him. COL Peoples had performed preclinical work showing that HER2 is a tumor antigen that can be recognized by cytotoxic T lymphocytes, which opened the door to the possibility that a vaccine could be given to augment that immune response against HER2. We continue to work together overseeing a large vaccine program that is investigating several vaccines targeting HER2 as well as vaccines targeting novel antigens to include folate binding protein, which is overexpressed in a variety of tumors, most notably ovarian cancer."
Following her tenure at Walter Reed, Dr. Mittendorf moved operations to the University of Texas M.D. Anderson Cancer Center. Coincidentally, it was at M.D. Anderson that COL Peoples had performed initial work on the vaccine in the lab of Dr. Constantine Ioannides, who, as the recipient of several BCRP awards, was homing in on the peptide that would serve as the basis for the specificity of NeuVax™.
Dr. Mittendorf recounts, "Dr. Ioannides performed much of the preclinical work evaluating E75. While COL Peoples was a fellow in surgical oncology at M.D. Anderson, he worked in Dr. Iaonnides' laboratory and ultimately helped Dr. Iaonnides - who is a basic scientist, not a clinician - translate the work to the clinic in the form of a phase I clinical trial."
NeuVax™ has two main components: a peptide derived from the HER2 protein (E75), and granulocyte-macrophage colony-stimulating factor (GM-CSF), an immunoadjuvant to potentiate the patient's immune response. This vaccine, which educates the patient's cytotoxic T lymphocytes to recognize and target tumor cells expressing the HER2 protein is minimally toxic, with most patients experiencing only redness at the injection site. Such a vaccine represents an appealing strategy in that it can stimulate a lifelong antitumor immune response that persists, even when treatment is completed.
A phase II clinical trial for NeuVax™ has already shown promising results. Of the 182 patients that are participating in the trial, 106 received the NeuVax™ vaccine and were compared to 76 controls who did not. At 24 months, disease free survival (DFS) was 94.3% in the vaccinated group and 86.8% in the control group. And the benefit from NeuVax™ is considered to be an underestimate of the vaccine's full potential, as 65% of the patients received a lower than optimal vaccine dose due to trial design.
It has been more than a decade since the early days of Dr. Mittendorf's collaboration with COL Peoples. NeuVax™ has come a long way. The phase II trial showed at two years that patients whose tumors have low HER2 expression mount a more robust immunologic response after vaccination than do patients whose tumors overexpress HER2 at high levels. Some of these patients showed decreased E75-specific immunity and a higher risk of relapse. As a result, Dr. Mittendorf and colleagues initiated a vaccine booster program. The booster was shown to be safe and, among patients receiving it, none have recurred, compared with a recurrence rate of 13.2% among controls.
Galena Biopharma, who holds the license to NeuVax™, is currently recruiting for a phase III trial that will enroll 700 patients internationally with patients that have low HER2 expression and are node-positive or have at least some cancer cells in the lymph nodes. With support from an FY13 BCRP Breakthrough, Funding Level 3 Award that was recently recommended for funding, Dr. Mittendorf is about to begin recruiting for a phase II trial evaluating NeuVax™ in patients that express HER2 at high levels (i.e., 3+ immunohistochemistry and designated clinically HER2-positive) and are being treated with trastuzumab. This trial is based on encouraging results from earlier trials, to include the E75 phase II trial, evaluating MHC class I vaccines: 55 patients with HER2 3+ tumors who have received trastuzumab and then NeuVax™ have shown no recurrences after 3 years. "We're just getting started on the work funded by this BCRP award, but it's an exciting project investigating a potential way to enhance response to vaccination and broaden the number of patients who may benefit from the vaccine."
Mittendorf EA, Clifton GT, Holmes JP, Clive KS, Patil R, Benavides LC, Gates JD, Sears AK, Stojadinovic A, Ponniah S, and Peoples GE. 2012. Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: From US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 118(10):2594-2602.