It’s unlikely that a simple approach like a peptide vaccine that stimulates a T-cell response against a single antigen would be effective in the metastatic setting. We now have ideas about how to use vaccines in combinations with other therapies to address this limitation.
Elizabeth A. Mittendorf, MD, PhD
Vaccines for both secondary and primary prevention of breast cancer are showing potential in clinical trials, according to Elizabeth A. Mittendorf, MD, PhD, who is leading much of the vaccine research at the University of Texas MD Anderson Cancer Center, Houston. Vaccine platforms being explored include dendritic cell vaccines, whole tumor cell vaccines (allogeneic, autologous), recombinant protein vaccines, peptide vaccines, DNA vaccines, and recombinant viral vectors. The focus of Dr. Mittendorf’s research has been peptide vaccines, which she described at the 2016 Miami Breast Cancer Conference.1
Peptides are derived from immunogenic proteins. They can be combined with an immunoadjuvant and given as a simple injection, which stimulates peptide-specific immune responses. “They are simple to construct, very easy to manufacture, inexpensive, and would be ‘off-the-shelf’ therapy that’s easily exportable to the community,” revealed Dr. Mittendorf, Associate Professor in the Department of Breast Surgical Oncology at MD Anderson.
Current peptide vaccines have profited from lessons learned 2 decades ago in metastatic disease, where they were not effective, presumably because of diffuse disease. “It’s unlikely that a simple approach like a peptide vaccine that stimulates a T-cell response against a single antigen would be effective in the metastatic setting,” she explained. “We now have ideas about how to use vaccines in combinations with other therapies to address this limitation.”
The vaccine strategy will probably be dictated by disease stage. For primary prevention in high-risk patients, vaccines alone might be effective. For minimal disease (ie, in the adjuvant setting), they might be effective alone or in combination with other immunomediated treatments for preventing recurrences. For patients with metastatic disease, vaccines alone are not likely to be effective but may be effective when combined with more aggressive strategies such as checkpoint blockade drugs, added Dr. Mittendorf.
HER2-Derived Peptide Vaccine
Encouraging results are coming in for her groups’ E75 HER2-derived peptide vaccine, nelipepimut-S (NeuVax), in early-stage breast cancer patients. E75 is a peptide from the extracellular domain of HER2. It directs activity against the HER2 protein by stimulation and activation of cytotoxic T lymphocytes and CD8-positive memory cells against the human leukocyte antigen (HLA)-presented HER2 epitope. The vaccine has high affinity for HLA-A2/A3; therefore, patients with this HLA profile are most likely to benefit.
A disease-free survival benefit was observed in a phase II trial of 187 early-stage breast cancer patients deemed at high risk for recurrence. Patients received six injections of E75 with granulocyte macrophage colony-stimulating factor (GM-CSF) after tumor resection (with or without chemotherapy and/or radiotherapy, as indicated).
The 5-year disease-free survival rate was 89.7% for the vaccinated group vs 80.2% for the controls (P = .08), which increased to 94.8% vs 80.2% (P = .05) among the optimally dosed cohort.2 Immune responses were observed on in vitro and in vivo assays.
Response rates were greater among patients with increased levels of cytotoxic T lymphocytes induced by E75. Recurrences were observed in only 1 of 30 patients (3%) with cytotoxic T lymphocytes above the mean, compared with 8 of 56 (14%) for patients with levels of cytotoxic T lymphocytes below the mean.3
The phase III registration PRESENT trial is evaluating E75 in 758 early-stage, node-positive HLA-A2/A3 patients with low to intermediate HER2 expression who received a complete response to standard treatment. Patients are randomized to E75 or placebo plus GM-CSF, receiving six injections monthly for 6 months, followed by a booster vaccination every 6 months for 3 years. The primary endpoint is disease-free survival at 3 years.
Strategies to Augment Response
Researchers believe that the booster is necessary for restimulating immunity and has been shown to reduce recurrences in early-phase trials. Other strategies to augment response include multiepitope vaccines (adding other class 1 epitopes or incorporating peptides stimulating a CD4-positive T-cell response), combination immunotherapy with trastuzumab (Herceptin), and combination therapy with “immunogenic” chemotherapy.
Dr. Mittendorf and her team are evaluating GP2, a class I epitope derived from the HER2 transmembrane domain, which works similarly to E75 by stimulating CD8-positive T cells. In a phase I/II trial of 190 patients with varying HER2 levels, the disease-free survival rate for patients who completed the series was 94%, vs 85% for controls—a 57% reduction in risk.4
For 48 patients who received the GP2 vaccine after receiving trastzumab, none had recurred by 4 years. This finding supports the concept that better results can be achieved when vaccines are combined with other immunomediating drugs, with trastuzumab being one, she said.
Dr. Mittendorf and her colleagues are now conducting a randomized multicenter phase II study evaluating combination immunotherapy with the E75/GM-CSF vaccine plus trastuzumab in high-risk HER2-positive patients. Patients not achieving a pathologic complete response after neoadjuvant chemotherapy plus anti-HER2 agent and patients having upfront surgery who are pathologically node-positive are eligible. Invasive disease–free survival is the primary endpoint.
“This population has about a 20% risk of recurrence within 3 years, and we think we can improve upon this with the vaccine,” she explained.
Other Combination Approaches
Also being evaluated is an allogeneic vaccine engineered from a HER2-positive cell line genetically modified to secrete GM-CSF, which is administered with trastuzumab and cyclophosphamide. In a feasibility study of 20 patients with HER2-positive metastatic disease, this combination appeared to be safe and was associated with a 40% clinical benefit rate. Correlative studies demonstrated expansion of HER2-specific CD8-positive T cells and an increase in HER2-specific delayed-type hypersensitivity in 33%. A phase II trial has been enrolled.
Dr. Mittendorf clarified that in the metastatic setting, vaccines may be ineffective alone, but in combination they could be effective. “The strategy they are working on here may make the vaccine effective, as it’s modified to secrete cytokines and is given with an immune-modulating dose of cyclophosphamide to decrease hostile regulatory T cells, and with trastuzumab, which has immunomodulatory activity.”
Researchers at the National Cancer Institute are also evaluating PANVAC, a poxviral-based cancer vaccine that includes transgenes for CEA and MUC-1 and the T-cell costimulatory molecules B7.1, ICAM-1, and LFA-3. In a phase II trial in metastatic breast cancer, patients randomized to receive PANVAC plus docetaxel had a median progression-free survival of about 8 months, vs about 4 months for docetaxel alone.5
Combinations of vaccines with immune checkpoint inhibitors are also in development, she added.
Vaccines for Primary Prevention
Researchers are also pursuing the concept of using vaccines for primary prevention. Researchers from the National Cancer Institute (NCI) recently offered a “roadmap” for this endeavor.6
One of their concepts revolves around restimulating immune responses first observed after childhood illness. It has been shown that children who have multiple infectious diseases and/or febrile illnesses in childhood are less likely to develop cancer. Their immune response, initially stimulated against epithelial antigens, can be restimulated at the first signs of a precancerous condition, such as advanced adenomas (for colorectal cancer) or ductal carcinoma in situ (for breast cancer), possibly to prevent progression.
“You give the vaccine when there’s a precursor lesion and augment the immune response to eliminate the tumor,” explained Dr. Mittendorf.
In a feasibility study, a vaccine targeting the MUC1 in individuals with advanced adenomas elicited high levels of anti-MUC1 IgG in 44% of patients.7 Nonresponders had increased levels of myeloid-derived suppressor cells, which promote tumor growth.
“This suggests an immunosuppressive environment was already in place in patients developing premalignant disease,” she said, which raises a few questions: Should we vaccinate even earlier? Can we use myeloid-derived suppressor cells to select patients for prophylactic vaccination? Can we target myeloid-derived suppressor cells at the time of vaccination?
In breast cancer, the precursor would be ductal carcinoma in situ or atypical ductal hyperplasia. It is possible that vaccination before tumor cells become genetically unstable and begin dividing rapidly could prevent evolution to malignancy.
A small study of a dendritic vaccine given neoadjuvantly demonstrated an immune response along with a reduction in HER2 expression in the tumor.8
Dr. Mittendorf and colleagues are exploring this concept in a phase II NCI-sponsored primary prevention study of the E75 vaccine in patients with ductal carcinoma in situ. Subjects will receive three doses preoperatively and then finish the series with three doses postoperatively. The endpoint is generation of E75-specific cytotoxic T lymphocytes. They will also evaluate for epitope spreading (ie, enhanced immune response to different antigens).
“We think it’s the broad immune response not only to the antigen we are vaccinating with, but also to other antigens that speaks to why vaccines could be effective,” she concluded. “By vaccinating patients in early-phase disease, we may be giving them long-lasting immunity to protect them down the line.” ■
Disclosure: Dr. Mittendorf has received institutional funding from Galena Biopharma (the maker of NeuVax) and Antigen Express.
1. Mittendorf EA: Immunotherapy update: Biology and early results: Vaccines. 2016 Miami Breast Cancer Conference. General Session. Presented March 11, 2016.
2. Mittendorf EA, Clifton GT, Holmes, JP, et al: Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol 25:1735-1742, 2014.
3. Schneble EJ, Berry JS, Trappey FA, et al: The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: Correlation of immunologic data with clinical response. Immunotherapy 6:519-531, 2014.
4. Schneble EJ, Perez SA, Murray JL, et al: Primary analysis of the prospective, randomized, phase II trial of GP2+GM–CSF vaccine versus GM–CSF alone administered in the adjuvant setting to high-risk breast cancer patients. 2014 Breast Cancer Symposium. Abstract 134.
5. Heery CR, Ibrahim NK, Arlen PM, et al: Docetaxel alone or in combination with a therapeutic cancer vaccine (PANVAC) in patients with metastatic breast cancer: A randomized clinical trial. JAMA Oncol 1:1087-1095, 2015.