news on her2 peptide vaccine from Journal of NCI

[Lani]

Oxford Journals
Medicine & Health
JNCI J Natl Cancer Inst Volume 107, Issue 210.1093/jnci/djv022


New Peptide Vaccine for HER2-Expressing Breast Tumors

Rochman Sue

A new HER2-derived peptide vaccine called GP2 reduces risk of breast cancer recurrence in patients whose tumors have any degree of HER2 expression—especially for HER2+ tumors.

Elizabeth Mittendorf, M.D., Ph.D., associate professor of surgical oncology at the University of Texas M. D. Anderson Cancer Center in Houston, led the phase II randomized trial that made this finding. She presented the study at last September’s American Society of Clinical Oncology Breast Cancer Symposium.

The phase II GP2 vaccine trial enrolled patients “with any degree of HER2 expression on IHC,” Mittendorf said, referring to the immunohistochemistry test used to determine a breast tumor’s level of HER2 expression. Tumors with a normal level of HER2 protein are scored 0–1+ and classified HER2–. Tumors with a moderate HER2 level are scored 2+ and sent for more testing to determine treatment. Tumors with a high HER2 level are scored 3+ and considered HER2+. A patient with an HER2+ tumor is a candidate for trastuzumab (Herceptin), which targets HER2. About 15%–20% of breast tumors are HER2+.

GP2 is given monthly for 6 months, followed by four cycles of booster shots every 6 months. Because it is a major histocompatibility complex (MHC) class I peptide that stimulates CD8+ T cells, GP2 can work only in patients who carry the allele for human leukocyte antigen (HLA)-A2 or HLA-A3. To enter the study, a patient had to be HLA-A2+ and have no evidence of disease after completing standard breast cancer treatment.


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HER2+ Patients Have Highest Response

In the study, 180 patients were randomly assigned to receive the GP2 vaccine plus granulocyte–macrophage colony-stimulating factor (GM-CSF) or to receive GM-CSF alone (the control group). The analysis looked at disease-free survival (DFS) for all patients. It also looked at a prespecified subgroup of the HER2+ (IHC 3+) patients—all of whom had received trastuzumab as part of their treatment.

The intention-to-treat analysis of the 180 patients after a median follow-up of 34 months showed 88.1% DFS in the 89-patient vaccine group and 81% in the 91-patient control group, a relative risk reduction of 37%. The per treatment analysis of 170 patients showed 93.5% DFS in the 83-patient vaccine group and 85% in the 87-patient control group, a relative risk reduction of 57%.

Patients with HER2+ tumors benefited most. The subgroup analysis of HER2+ patients found 100% DFS in the 48 patients who received the vaccine after completing trastuzumab and 88.8% in the 50 who received GM-CSF alone.

“This is not a trivial number of patients who have not had a recurrence,” Mittendorf said. It also “suggests a mechanism of synergy between the vaccine and trastuzumab that comes from using two different ways to get the immune system to see HER2 as foreign.”

Other researchers agreed that the science and results were interesting, although some had questions about the HER2-positive patients.

“The numbers are too small to draw a conclusion without knowing specifics about the HER2+ patients who had a recurrence and those who did not, and whether those arms were balanced in terms of tumor size and nodal status,” said Edith A. Perez, M.D., deputy director at large at the Mayo Clinic Cancer Center in Jacksonville, Fla.

Dennis Slamon, M.D., Ph.D., director of clinical/translational research at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center—whose research led to developing trastuzumab—said that seeing the hormone status of the patients in the subgroup analysis would be important.

“Patients who are ER– have higher response rates to trastuzumab than those who are ER+,” Slamon said. “If there was an imbalance in those HER2 subgroups, that could account for the differences seen.”

Previous Section

Finding Supports Previous Research

Results of the new primary analysis support those of previous studies.

“It is pretty accepted throughout the immunotherapy research community that giving trastuzumab along with the vaccine or prior to the vaccine primes the T cells—whether the vaccine targets CD4+ or CD8+ T cells,” said Lupe G. Salazar, M.D., assistant professor of medicine in the tumor vaccine group at Seattle’s University of Washington School of Medicine.

“HER2 expression is not as important for generating an immune response to an HER2 vaccine as it is for generating a response to a monoclonal antibody, like trastuzumab, which requires an IHC 3+ score,” she said. This is why researchers believe an HER2 peptide vaccine could benefit pa- tients who are not HER2+. (A phase III trial of the HER2 peptide vaccine NeuVax is enrolling patients with an IHC score of 1+ or 2+.)

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Dennis Slamon, M.D., Ph.D.

Researchers are also interested in IHC 1+ and 2+ patients because while the HER2 vaccines have been in trials, HER2-targeted therapies have expanded in number and in use.

Trastuzumab was first approved for use in the adjuvant setting in 2006. The initial approval was for early-stage HER2-positive, node-positive breast cancer; the approval was expanded in 2008 to include node-negative patients with one high-risk feature. A recent joint analysis of the NSABP B-31 and NCCTG N9831 randomized phase III trials that led to these approvals showed that adjuvant trastuzumab added to chemotherapy increased 10-year overall survival from 75.2% to 84% and 10-year DFS from 62.2% to 73.7%, Salazar said. “So the question becomes, if you add the vaccine to trastuzumab to prevent recurrence, does it improve survival even more? And with this vaccine, it’s limited to those who are HLA-A2+, so that’s a small pool of breast cancer patients.” (About 40%–55% of the population has the HLA-A2 allele.)

Mittendorf acknowledged that obstacles to bringing a HER2 vaccine forward exist.

“The HER2 space is crowded,” she said. “Trastuzumab is no longer the only player. There is TDM-1 (Kadcyla). There is pertuzumab (Perjeta). These agents are being tested in the neoadjuvant and adjuvant setting. We will need to further investigate and see who really needs what. [HER2-targeted] therapies are expensive regimens” to combine, and they have side effects. The vaccine is nontoxic, is very inexpensive and might stimulate a memory response that would work against HER2 for life.”

And that excites researchers.

“The logic to test these vaccines is there and the potential is definitely there,” Slamon said. “It’s been known for a long time you that you could get an immune response to what you are immunizing against. But just because you can measure an immune response doesn’t mean it will translate into a clinical response or clinical benefit. You only know that by looking at clinical outcomes and that takes time.”

Norwell owns the GP2 vaccine. Mittendorf is the principal investigator on vaccine trials that Galena Biopharma (NeuVax), Antigen Express (AE37), and Norwell sponsored. The M. D. Anderson Cancer Center receives financial support for each study patient enrolled. George E. Peoples Jr., M.D., F.A.C.S., a coauthor of the GP2 study, holds inventor rights to GP2.

© Oxford University Press 2015.

[Mtngrl]

This is exciting news.

I hope it gets further study and continues to show good results.