Evaluation of Plasmid DNA Vaccine Encoding HER2 Intracellular Domain in Patients With Advanced HER2-Positive Breast Cancer

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In a single-institution phase I study reported in JAMA Oncology, Disis et al found that a plasmid DNA vaccine encoding the HER2 intracellular domain (ICD) was associated with primarily low-grade toxicity and induced HER2-specific type 1 T-cell responses in patients with advanced HER2-positive breast cancer.

As stated by the investigators, “High levels of HER2-specific type 1 T cells in the peripheral blood are associated with favorable clinical outcomes after trastuzumab therapy; however, only a minority of patients develop measurable HER2 immunity after treatment. Vaccines designed to increase HER2-specific T-helper cells could induce HER2 immunity in a majority of patients.”

Study Details

The study involved 66 patients with stage III/IV disease treated at Fred Hutchinson Cancer Center between 2001 and 2010, with a 10-year postvaccine toxicity assessment. Patients received three intradermal immunizations with the HER2 ICD vaccine 1 month apart, together with soluble granulocyte-macrophage colony-stimulating factor as an adjuvant, at doses of 10 (n = 22), 100 (n = 22), and 500 μg (n = 22).

Toxicity evaluations occurred at defined intervals and yearly. Peripheral blood mononuclear cells were collected for evaluation of immune response, and biopsy of vaccine sites at weeks 16 and 36 were used to measure plasmid DNA persistence at the sites.

Key Findings

Overall, treatment-related grade 1 and grade 2 toxicities occurred in 98% and 44% of patients, respectively, with only 1 grade 3 event observed (in the 500-µg group); no significant differences in incidence of treatment-related toxicity were observed among groups. The most common adverse events were injection site reactions (82%), fatigue (36%), and flu-like syndrome (33%).

Patients in the 100-μg group (P = .003) and those in the 500-μg group (P < .001) had higher-magnitude HER2 ICD type 1 immune responses at most time points vs the 10-μg group after adjustment for baseline factors.

Data on plasmid DNA persistence at week 16 was available for 53 patients; 32 patients (60%) had detectable DNA in the skin, including 11 (61%) of 18 in the 10-µg group, 10 (50%) of 20 in the 100-µg group, and 11 (73%) of 15 in the 500-µg group. At follow-ups after the end of immunizations, relative to baseline, HER2 ICD responses were significantly lower on average in patients with vs without DNA persistence at week 16 (P = .02). Analysis at 36 weeks in 44 patients showed persistence at the vaccine site in 4 (31%) of 13 patients in the 10-µg group, 2 (10%) of 20 in the 100-µg group, and 11 (92%) of 12 in the 500-µg group—confirming a higher frequency of persistence at the highest dose.   

The investigators concluded, “In this phase I nonrandomized clinical trial, immunization with the 100-μg dose of the HER2 ICD plasmid-based vaccine was associated with generation of HER2-specific type 1 T cells in most patients with HER2-expressing breast cancer, and it is currently being evaluated in randomized phase II trials.”

Mary L. (Nora) Disis, MD, of the University of Washington Medicine Cancer Vaccine Institute, University of Washington, Seattle, is the corresponding author for the JAMA Oncology article.

Disclosure: This study was supported by grants from the National Cancer Institute and National Institutes of Health. For full disclosures of the study authors, visit

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