MIAMI BEACH – Vaccines are an appealing therapeutic strategy for cancer because they are specific and have minimal associated toxicity, according to Dr. Elizabeth A. Mittendorf.
Further, they stimulate the adaptive immune system, thereby eliciting a memory response that allows for sustained effect, she said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.
For these reasons, there is a great deal of interest in the possibility of a breast cancer vaccine, she said.
No such vaccine has been approved, but several vaccines, as well as treatment strategies employing the investigational vaccines, are currently in clinical trials, she said.
One – E75 (nelipepimut-S) – is being evaluated in the ongoing PRESENT (Prevention of Recurrence in Early Stage Node-Positive Breast Cancers with Low to Intermediate HER2 Expression with NeuVax Treatment) phase III registration trial.
“E75 is a 9-amino-acid peptide in the protein’s extracellular domain. It’s what’s referred to as an immunodominant epitope of HER2; that simply means it’s the one that’s presented best and therefore [is] recognized most efficiently by the immune system. It’s a major histocompatibility complex (MHC) class I peptide, which means it’s going to stimulate a CD8+ T-cell response,” she explained, adding that E75 has “a high affinity for HLA-A2 and -A3, meaning that patients with those haplotypes are the ones most likely to benefit from vaccination.”
For the phase I and II trials, E75 was combined with granulocyte-macrophage colony-stimulating factor (GM-CSF). This “very simple vaccine strategy” was administered to prevent disease recurrence in patients with high-risk breast cancer.
“We’re vaccinating patients who have been rendered disease free with standard of care therapy to include surgery, chemotherapy, and, when indicated, radiation, with the goal being to prevent disease recurrence,” she said, noting that all patients had histologically confirmed breast cancer and were either node positive or high-risk node negative.
The original primary endpoint of the study was disease-free survival at 18 months, but encouraging data led to an extension of that out to 5 years.
A combined analysis of the phase I and II trials included 187 evaluable patients, who had an overall 90% rate of 5-year disease-free survival, compared with 80% among controls. The difference, which represented about a 50% relative risk reduction was statistically significant, Dr. Mittendorf said.
Among patients who received optimal dosing, the 5-year disease-free survival rate was 95%, she added.
E75 has now been licensed and the E75-GM-CSF combination is known as NeuVax. For the PRESENT III trial, the treatment is administered in the adjuvant setting in node-positive HLA-A2 and -A3 patients with low or intermediate HER2-expressing tumors.
Patients were randomized to receive six shots monthly for 6 months of either the combination or GM-CSF alone, followed by booster inoculations every 6 months for 3 years.
The trial has completed accrual and randomization, and includes 750 patients.
“The goal is to look at disease-free survival at 3 years, so the study should read out in the Spring of 2018,” she said.
In the meantime, efforts are underway to identify strategies – such as use of booster inoculations similar to those used in the PRESENT III trial – to augment response to vaccination, and to develop a multiepitope vaccine involving peptides that stimulate a different CD8+ T-cell response or CD4+ T-cell response.
“We’ve been very interested in the idea of the combination of immunotherapy with trastuzumab, and combination therapy with immunogenic chemo ... so based on the preclinical and scientific rationale, as well as the observation in our previous study, we’re moving forward now with a phase II trial looking at combination therapy with a class I vaccine in combination with trastuzumab in high-risk HER2-positive patients,” Dr. Mittendorf said.
Patients will be randomized to receive trastuzumab plus vaccine or trastuzumab alone, which is the current standard of care, and the primary end point is disease-free survival. The trial is currently enrolling patients and is about a third accrued.
Additional strategies being investigated include allogeneic vaccines, viral vaccines, and others, she said.
The use of vaccines for primary cancer prevention is also of great interest, Dr. Mittendorf said, noting that because of the success with E75, her group has been asked by the National Cancer Institute to conduct a trial in patients with ductal carcinoma in situ “as a first step toward moving into prevention.”
“About 2 weeks ago, we had the site initiation visits for the VADIS trial. This is a phase II trial of nelipepimut-S (E75, NeuVAX),” she said.
For that trial, patients with DCIS will be vaccinated with three doses before surgery, and with three in the postoperative period. The primary endpoint is the generation of E75-specific cytotoxic T lymphocytes; the study will also include a number of secondary endpoints, including epitope spreading.