Priming HER2 breast cancer with a vaccine to improve PD-1 inhibition

Immune checkpoint inhibitors such as Roche’s Tecentriq and Merck & Co.’s Keytruda have shown efficacy in triple-negative breast cancer, but their anti-tumor activity in the HER2-positive subtype remains limited.

Now scientists at Duke University have demonstrated that priming the immune system with a vaccine boosts the activity of existing PD-1/L1 checkpoint inhibitors in mouse models of HER2-positive breast cancer. Combining a vaccine targeting an oncogenic variant of HER2 that lacks exon 16 (HER2D16) with an anti-PD-1 antibody cleared tumors in the mice and led to prolonged survival, according to results published in the journal Clinical Cancer Research.

The promising results have led to a phase 2 clinical trial that’s testing a similar HER2 vaccine, called VRP-HER2, in combination with Keytruda in patients with advanced HER2-overexpressing breast cancer.

Unlike triple-negative breast cancer, HER2 breast cancer generally contains fewer antigenic elements that the immune system can recognize and fewer tumor-infiltrating T cells. That partly explains why unleashing the full power of the immune system with a PD-1/L1 blocker still doesn’t work well in this subtype of cancer.

Using patient samples, the Duke team confirmed that HER2D16 expression can impede HER2-targeting therapies, including Roche’s Herceptin and Kadcyla. Therefore HER2D16 may represent an important signaling mechanism that causes HER2-positive tumors to resist drug therapies, making it a good target for immunotherapy, they argued.

The team designed an adenovirus-vectored vaccine against HER2D16. In mice, a single vaccination triggered strong HER2-specific T-cell and antibody responses, which slowed tumor growth. However, the vaccine by itself couldn’t eradicate the tumors. The researchers suggested that the PD-1/L1 immunosuppressive mechanism was to blame, leading them to test a combination of the vaccine and an anti-PD-1 attack.

“The basic premise is that the immune checkpoint inhibitors work fantastic if the body has already triggered an immune response, but they don’t work well in the absence of that,” Kim Lyerly, an author of the study, explained in a statement.

While HER2-positive breast cancer didn’t respond to solo PD-1 in a mouse model, the combo achieved significant improvement in survival, with about 30% of mice experiencing complete tumor regression and more than 150 days of long-term tumor-free survival, the team reported. Further analysis revealed that the vaccination not only induced systemic immune responses, but also enhanced HER2-specific CD8 T cells that infiltrate into tumors.

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There has been increased interest in cancer vaccines, which aim to trigger an immune response against cancer. Scientists at the National Cancer Institute genetically modified dendritic cells from patients to produce parts of the HER2 protein as a vaccine.

A team at Arizona State University focused on frameshift peptides, which are proteins produced when errors occur during genetic information transfer from DNA to RNA in cancer cells. Breast cancer was one type that had large amounts of the peptides for potential vaccine design, the team found.

The Duke University scientists believe their study showed that a vaccine targeting HER2D16 is effective in eliciting antitumor T-cell responses, which can be further improved by an PD-1 inhibitor. A phase 2 trial is already testing the findings in humans with HER2-positive breast cancer. Although the current study has only examined the combo approach in breast cancer, future studies could include other HER2-positive cancer types such as gastric cancer, or even target other oncogenes, the researchers wrote in the study.