Experimental breast cancer vaccine generates immune response to key tumor protein
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An experimental plasmid DNA vaccine produced a strong immune response to the HER2 protein among women with advanced HER2-positive breast cancer, according to results of a single-arm, phase 1 study published in JAMA Oncology.
The vaccine also appeared safe and immunity persisted after vaccinations ended, researchers wrote.
Background
Although high amounts of HER2 (also known as ERBB2)-specific type 1 T cells in peripheral blood have been associated with positive outcomes after treatment with trastuzumab (Herceptin, Genentech), few patients subsequently build measurable HER2 immunity. Vaccines that boost HER2-specific T-helper cells may induce HER2 immunity in most patients, researchers wrote.
“Vaccines will stimulate T cells, which can be programmed to hunt down the last remaining [cancer] cells in the body and kill them,” Mary L. “Nora” Disis, MD, professor of medicine at University of Washington and director of University of Washington Cancer Vaccine Institute, told Healio. “Stimulating effective immunity is the only way I know we can sterilize the body from all breast cancer cells. HER2 is an immunogenic protein in breast cancer and is an excellent target for the immune system.”
Methodology
Disis and colleagues sought to evaluate the immunogenicity and safety of an HER2-targeted plasmid-based vaccine among 66 patients (median age, 51 years; range, 34-77) with stage III and stage IV HER2-positive breast cancer. Patients underwent treatment between 2001 and 2010 at an academic medical center and had 10-year postvaccine toxicity evaluations. They had no evidence of or bone-only disease after completion of standard therapy or HER2 tumor overexpression, had not received chemotherapy or immune-suppressing drugs 30 days prior to enrollment, and had normal left ventricular ejection fraction.
Researchers divided patients into three cohorts that each received three vaccine injections: low dose (10 µg), intermediate dose (100 µg) and high-dose (500 µg). All patients also received granulocyte-macrophage colony-stimulating factor, which promotes cytotoxic immunity.
Safety and HER2 intercellular domain immune responses served as the main outcomes. Secondary objectives included determination of whether vaccine dose correlated with immunity and plasma DNA persistence at the vaccine site.
Median follow-up was nearly 10 years (range, 3-13).
Results
The vaccine stimulated the desired cytotoxic immune response without severe toxicities, according to researchers.
Vaccine-related adverse events, mostly grade 1 or grade 2, did not differ significantly among the cohorts. After adjustment for baseline factors, researchers observed a higher degree of HER2 intercellular domain type 1 immune responses at a majority of time points in the intermediate- vs. low-dose cohort (coefficient, 181; 95% CI, 60-303; P = .003) and high- vs. low-dose cohort (coefficient, 233; 95% CI, 102-363; P < .001).
Patients with DNA persistence at week 16 had significantly lower HER2 intercellular domain immunity on average than those without DNA persistence. The highest vaccine dose appeared associated with the highest persistent DNA incidence at the injection site.
“New vaccine technologies such as DNA based immunization have the potential to create high levels of long-lasting immunity — which we showed in this trial,” Disis said.
The degree of difference in the ability to generate immunity among the doses surprised Disis. “It taught me it is important to find the right dose of vaccine to move forward with larger trials,” she said. “The second surprise was how well patients did. Despite having very advanced, and in some cases metastatic disease, the survival after 8 years of follow-up was over 75%, with many patients not yet experiencing a disease recurrence.”
Next steps
The next step will be to evaluate the vaccine in a phase 2 study, Disis said.
“We will randomize HER2-low patients to receive the vaccine or an immune-stimulating agent,” Disis said. “The endpoint will be whether we do prevent disease recurrence. ... I think there is a good chance we can see vaccines in the clinic in about 5 years. Clinical trials of breast cancer vaccines given alone or with other treatments have increased by about 25% in the last several years.”
For more information:
Mary L. “Nora” Disis, MD, can be reached at University of Washington and Fred Hutchinson Cancer Center, 850 Republican St., Brotman 221, Box 358050, Seattle, WA 98109-4725; email: ndisis@uw.edu.
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