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ASCO: AE37 Peptide Vaccine May Help Prevent Breast Cancer Recurrence

  • Anna Azvolinsky
Jun 12, 2012
  • Breast Cancer, ASCO 2012, ASCO Breast Cancer, HER2-Positive Breast Cancer

Women previously treated for HER2-positive breast cancer have lower rates of relapse when given a novel peptide vaccine. The AE37 vaccine showed a 43% risk reduction in these patients after 22 months of follow-up in a phase IIb clinical trial. Recurrence rates were 10.3% among women inoculated with the vaccine compared to 18% of women in the control group.

Internal mammary node recurrence, after mastectomy; source: Tdvorak, Wikimedia Commons

A stronger reduction in relapse frequency was seen among patients with lower levels of HER2 on their tumors, a population that is currently not eligible for trastuzumab therapy. These lower HER2-expression patients had an 11% rate of relapse when given the vaccine compared to 31% in the control group. These results were presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These phase II trial data are exciting and warrant a phase III trial to further evaluate efficacy,” said principal investigator, Dr. Elizabeth Mittendorf, a surgical oncologist at MD Anderson Cancer Center in Houston. Antigen Express, the company that developed the vaccine plans for a phase III trial to begin by the end of 2012. The vaccine has the potential to improve recurrence rates and has been well tolerated, according to researchers.

Why the AE37 Vaccine May Be Unique

The development of the AE37 peptide vaccine stems from evidence suggesting peptides containing major histocompatibility complex (MHC) Class II epitopes. MHC molecules are expressed on certain immune cells and mediate autoimmunity as well as compatibility of donors for organ transplants. These MHC Class II molecules elicit CD4+ T-cell responses—these are white blood cells that help trigger immune responses to foreign antigens.

Essentially, the AE37 vaccine stimulates the immune system and CD4+ T-helper cells to recognize the HER2 protein—expressed on HER2-positive breast tumors—as 'foreign.' The vaccine links together a peptide of HER2 (AE36), a unique peptide that is based on an immune-regulatory protein called li-Key peptide. In the laboratory, this vaccine was found to increase the potency of the vaccine 250-fold.

“The most unique aspect is that AE37 is a Ii-Key Hybrid peptide that is MHC Class II-associated and elicits a CD4+ T-cell response,” said Dr. Timothy J. Vreeland, a resident at the Brooke Army Medical Center in San Antonio, Texas, and presenter of the research at the this year's ASCO meeting. “Until recently the vast majority of cancer vaccine research has been focused on the MHC Class I molecule because the tumor cells themselves have Class I molecules.” Because the vaccine induced a CD4+ T-cell response, this causes a more robust immune response, Vreeland explained. Helper T-cell involvement is likely important, and depends on the li-Key peptide in this vaccine, according to Vreeland, who added that there has not been success with MHC Class II peptides prior to this vaccine.

Data presented at the 2012 American Association for Cancer Research showed that the AE37 vaccine is not stimulating CD4+ CD25+ regulatory T cells, which are known to be immunosuppressive. “[This is] obviously a good thing,” said Dr. Mittendorf.

AE37 has the potential to serve an unmet need—those women whose tumors express lower levels of HER2, for which trastuzumab (Herceptin) is not indicated.  While women whose tumors overexpress HER2—approximately 25% of all breast cancer patients—are treated with trastuzumab, the other patients, whose tumors have lower levels of HER2 are only eligible for hormonal or chemotherapy treatments. According to Dr. Vreeland, this vaccine appears to be effective in the roughly 60% of breast cancer patients who have intermediate levels of HER2 and are not eligible for trastuzumab. So far, the data demonstrate that the vaccine is likely to be more effective in this low to moderate HER2 level population.

“I anticipate that there are a lot of patients for a phase III trial, particularly patients with low to mid HER2-positive disease as they represent an unmet clinical need,” Mittendorf said.

The ongoing patient phase II trial is comparing the AE37 vaccine plus granulocyte-macrophage colony-stimulating factor (GM-CSF) to GM-CSF alone. GM-CSF is a peptide secreted by different immune cells and an immune stimulant. All women enrolled on the trial had standard therapy and were disease-free before starting the trial. Patients’ immune response dynamics are monitored on the trial to gather data to better predict those patients who are likely to recur in the future and whose immune systems respond to the vaccine.

Patients enrolling in the trial can have any level of HER2 expression. Each vaccine is given every 3 to 4 weeks for a total of six intradermal injections. Both Vreeland and Mittendorf believe that a cancer vaccine is most likely to be effective in preventing recurrence, when patients are relativel disease-free, rather than treating active disease.

Could the AE37 vaccine, and other vaccines in development be extended to other patient populations? “There is a theoretic possibility of extending this treatment to patients who do not have cancer, but are at risk,” said Vreeland. Ductal carcinoma in situ patients, for example, who have noninvasive disease, but may be at risk for progression to invasive disease. The caveat, according to Vreeland, would be the difficultly in execution of a trial with early-stage or disease-free patients because of the long-term trial length and the large number of patients required. Both of these factors would be necessary to show a difference in cancer rate development.

While previous therapeutic vaccine approaches for cancer patients have not worked, Mittendorf believes that the AE37 approach is different. “We are not using them as therapeutic vaccines to treat patients with established, metastatic disease—a scenario where peptide vaccines have previously been tried and not worked well,” Mittendorf explained. “There are many aspects of the metastatic microenvironment that are immunosuppressive which likely explains why that strategy has not been effective.”

AE37 is not the only peptide vaccine in development in the adjuvant setting. Galena BioPharma's NeuVax (E75) is currently in phase III trials for the treatment of various cancers. NeuVax is also derived from the HER2 protein but is MHC Class I restricted. Thus far, there is evidence of prevention of disease recurrence with NeuVax as well. Another vaccine, GP2 (which like E75 is a HER2-derived vaccine), is being developed by Antigen Express.

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