In women with metastatic breast cancer, an experimental vaccine against human epidermal growth factor receptor 2 (HER2) safely generated an immune response to the protein. This is according to results from a phase 1 non-randomized study published in JAMA Oncology.

Disis ML, Guthrie KA, Liu Y, et al. Safety and outcomes of a plasmid DNA vaccine encoding the ERBB2 intracellular domain in patients with advanced-stage ERBB2-positive breast cancer: a phase 1 nonrandomized clinical trial. JAMA Oncol. 2023;9(1):71–78.

 

 

Because this was not a randomized clinical trial, the results should be considered preliminary. However, as lead author Mary “Nora” L. Disis, MD, said, speaking for the news release about the study, “the findings are promising enough that the vaccine will now be evaluated in a larger, randomized clinical trial.”

Breast cancer vaccine safely generates anti-tumor immunity. News Release. UW Medicine. November 3, 2022.

 

This study is a step forward in the quest to develop an effective vaccine to treat patients with breast cancer.

 

Vaccine studies to date

 

Despite the disappointing results, researchers have gained valuable information on the clinical application of the vaccines, from the type of immune response needed to eradicate a tumor or induce type I T-cell immunity, to the patient populations for whom vaccination would be most beneficial. 

Some researchers have speculated that the anti-tumor immunity stimulated by vaccines does not last long enough to significantly affect survival.

Zhu SY, Yu KD. Breast cancer vaccines: disappointing or promising? Front Immunol. 2022;13:828386.

To overcome this issue, such factors as the optimal dose and schedule for immunization, delivery routes, and choice of immunologic boosters need to be investigated.

 

 

Vaccine targets: HER2 and ERBB2 ICD

 

HER2-targeted therapy is one avenue of investigation for a breast cancer vaccine.

Some patients mount an immune response to the high levels of HER2, and especially to overproduction of its erb-b2 receptor tyrosine kinase 2 (ERBB2) intracellular domain (ICD). This immune response, which is cytotoxic, is beneficial: it results in less chance of recurrence and longer overall survival. 

Favorable clinical outcomes after trastuzumab therapy have, in fact, been reported in patients with high levels of ERBB2–specific type 1 T cells in the peripheral blood, according to Dr. Disis and her investigative team. 

Only a minority of patients develop this ERBB2 immunity post-treatment, however. 

The investigators proposed that, if a vaccine were designed to increase ERBB2-specific T-helper cells, this could induce ERBB2 immunity in more patients.

To test this hypothesis, Dr. Disis and colleagues developed a DNA vaccine encoding the ERBB2 ICD. 

 

DNA vaccine: Phase 1 trial 

 

As reported in JAMA Oncology, Dr. Disis and her team tested the safety and the immunogenicity of the DNA vaccine at three different doses in a single-arm study. 

Study design

For the study, 66 women (median age, 51 years) with advanced-stage ERBB2-positive breast cancer were enrolled. All were treated at the University of Washington School of Medicine between 2001 and 2010. 

The participants were divided into three dose groups, to receive intradermal monthly vaccine injections of low-dose (10 μg), intermediate-dose (100 μg), or high-dose (500 μg) formulations. Each participant received three injections. Participants also received the immune-stimulating drug granulocyte-macrophage colony-stimulating factor, which promotes cytotoxic immunity. 

Median follow-up was nearly 10 years. The researchers evaluated toxicity at set intervals and yearly. Immunity was assessed via the collection of peripheral blood mononuclear cells, and vaccine sites were biopsied at weeks 16 and 36 to measure DNA persistence. 

Safety

Most of the adverse events related to the vaccine were grade 1 and 2 events and occurred with all doses.

The results showed that the vaccine was very safe.

“In fact, the most common side effects that we saw in about half the patients were very similar to what you see with COVID-19 vaccines: redness and swelling at the injection site and maybe some fever, chills and flu-like symptoms,” Dr. Disis said. 

Immune response

After adjustment for baseline factors, patients in the 100-μg group and the 500-μg group had higher-magnitude ERBB2 ICD type 1 immune responses than the 10-μg group at most time points. Immunity decreased with DNA persistence at the injection site, and the highest incidence of persistent DNA was seen with the highest vaccine dose.

In summing up the study results, the authors stated that immunization with 100 μg of ERBB2 ICD plasmid DNA was associated with generation of immunity in most patients, which persisted after the end of vaccinations.

 

Phase 2 study initiated

 

The vaccine is undergoing a phase 2 study. 

If the results of the new randomized, controlled phase 2 study of the vaccine are positive, “it will be a strong signal” to rapidly move forward to a definitive phase 3 trial, noted Dr. Disis.

I have high hopes that we’re close to having a vaccine that can effectively treat patients with breast cancer.

For more information or enrollment inquiries for the phase 2 study,  contact the patient coordinator at uwcvi@uw.edu or 206-543-3829