HER2-Derived Peptide Vaccine Cuts Recurrence in High-Risk Breast Cancer

Elizabeth Mittendorf, MD, PhD

A novel HER2-derived peptide (GP2) vaccine designed to stimulate CD8+ cytotoxic T-lymphocytes reduced the rate of breast cancer recurrence and proved safe and well tolerated in an adjuvant setting.

In a multicenter phase II randomized study of 180 women with high-risk breast cancer, GP2 vaccine recipients with the highest overexpression of HER2 had no recurrences after completing trastuzumab therapy. Results of the study were released by Elizabeth Mittendorf, MD, PhD, at the 2014 ASCO Breast Cancer Symposium.

The GP2 peptide is 9 amino acids long and binds to major histocompatibility complex (MHC) class I molecules to stimulate a CD8+ T-cell response. The GP2 vaccine therefore works only in patients who are positive for HLA-A2 or HLA-A3.

Once taken from HER2, GP2 is combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) to help stimulate an immune response. When the combination is injected, GM-CSF stimulates dendritic cells to take up and process GP2 so that it can be better presented to the immune system.

“Peptide vaccines have the benefit of being easy to construct and manufacture on a large scale, they’re inexpensive, and very importantly they are off-the-shelf therapy,” said Mittendorf, associate professor of surgical oncology at the University of Texas MD Anderson Cancer Center, Houston.

Preclinical studies have demonstrated immunogenicity of GP2, and a “phase I trial demonstrated it to be safe and capable of stimulating a HER2-specific immune response,” she said.

Women in the trial with HLA-A2+, node-positive, or high-risk node-negative breast cancer with any level of HER2 expression who were rendered disease-free with standard-of-care therapy were randomized to receive GP2 plus GM-CSF or GM-CSF alone. Patients received 6 monthly intradermal inoculations during the primary vaccination series followed by 4 boosters administered every 6 months. The median age of study participants was 51 years and slightly more than half had HER2 overexpression.

The majority of patients experienced grade 1 local toxicity, such as erythema and pruritus at the injection site. Most patients also experienced grade 1 systemic toxicity, usually fatigue, headache, bone pain, myalgias, or flu-like symptoms, which generally resolved after 4 hours or after administration of acetaminophen. The toxicity profile of patients who were vaccinated is comparable to that of patients who received GM-CSF alone, “suggesting that the toxicity is due to the GM-CSF immunoadjuvant,” said Mittendorf.

Anin vivoantigen-specific immune response was attained with vaccination, as determined by mean delayed-type hypersensitivity reaction.

Disease-free survival (DFS) analyses were performed on an intention-to-treat (ITT) basis, as well as on a population that excluded patients who recurred during their primary vaccination series and on those who developed a second non-breast malignancy. Two patients experienced early recurrence and 6 developed a second malignancy.

After a median follow-up of 34 months, the ITT analysis showed that the DFS rate was 88% among those who received the GP2 vaccine and 81% in the control group, corresponding to a 37% reduction in recurrence. Excluding the patients who recurred during their primary vaccination series or developed a second malignancy, the DFS rate for vaccinated patients was 94% compared with 85% in unvaccinated controls, a 57% reduction in risk of recurrence with the vaccine.

A prespecified subgroup analysis in patients with HER2-positive breast cancer demonstrated no recurrences when administered the GP2 vaccine after completing trastuzumab.

This trial investigated the sequential use of trastuzumab plus the vaccine, but concurrent use of the two may address the early recurrences, Mittendorf hypothesized. A phase I trial of concurrent use showed the combination to be safe, with no increase in local or systemic toxicity, including no increase in cardiac toxicity. Immune-mediated mechanisms of trastuzumab may explain the synergism, according to Mittendorf, including antibody-dependent cellular cytotoxicity, stimulation of antigen-specific CD4+ T-cell response, and HER2-specific antibody response. “Together, this promotes a broader anti-HER2 immune response, which could be potentially augmented with vaccination,” she said.

A phase II trial looking at combination immunotherapy with trastuzumab and a CD8 T-cell-eliciting vaccine in high-risk HER2+ breast cancer will begin enrolling patients.

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