New in OncoImmunology: Novel treatment for triple-negative breast cancer

September 25, 2017 | by City of Hope

Don Diamond, Ph.D., Chair, Dept. of Experimental Therapeutics Don J. Diamond, Ph.D.
City of Hope doctors and scientists have published a study in OncoImmunology about a triple-negative breast cancer patient whose disease regressed rapidly when she took part in an experimental treatment that combines an anti-p53 cancer vaccine, which was developed at City of Hope, and a drug that blocks a specific cancer-aiding protein.
The woman was diagnosed with triple-negative breast cancer in 2008. She had received various chemotherapy treatments and was in the late stages of the disease when she started the experimental treatment in the summer of 2016. Previous chemotherapy had failed to control cutaneous metastases or the malignant lesions on at least 50 percent of her body, which caused severe itchiness and pain.
The woman, who was 69 at the time, took the p53 vaccine and pembrolizumab. After two cycles of the novel therapy, her skin lesions had disappeared almost entirely, and a skin biopsy showed that the clusters of tumor cells directly under the skin had disappeared.
By December 2016, the woman’s skin had cleared up entirely.
“It was shocking to me,” said Don J. Diamond, Ph.D., City of Hope chair of the Department of Experimental Therapeutics and the study’s senior author, who examined the woman at the time. “What we have noticed is that her immune response to p53 has been increasing as time goes on. It was of tremendous magnitude in the [blood] draw, coincident with her striking remission.”
The treatment activated p53-specific T cell responses and increased the number of multiple immune response genes. Together, they had the effect of stopping the impact of cancer-causing genes.
Diamond and his team developed the vaccine because the most frequent genetic mutation in all cancers occurs in a gene called p53, which contributes to cells becoming oncogenic; they produce a mutant form of the p53 protein. The vaccine boosts the immune response to many different mutant forms of p53. The researchers tested this vaccine, known as p53MVA, in a 2013 clinical trial and found it to be safe in patients with advanced gastrointestinal cancers.
However, patients whose T cells had pre-existing high levels of a protein named PD1 — a molecule that instructs immune cells to shut down — responded poorly to the anti-p53 vaccine. In a subsequent laboratory study, City of Hope researchers showed that these patients’ immune cells could be reactivated by treatment with a PD1 inhibitor that is a biosimilar to the clinical drug called pembrolizumab.
Yuan Yuan, M.D., Ph.D., City of Hope breast oncologist Yuan Yuan, M.D., Ph.D.
The woman participated in a City of Hope clinical trial that tested the combination in solid tumors, and the trial is still recruiting participants. Yuan Yuan, M.D., Ph.D., a breast oncologist who was the study’s lead author, is leading the triple-negative breast cancer accrual effort of that clinical trial.
It was particularly heartening for City of Hope doctors and researchers that the treatment approach showed such a dramatic response in a triple-negative breast cancer patient.
That’s because triple-negative breast cancer, which represents approximately 15 percent of all breast cancers, is a particularly difficult disease to treat. Due to the lack of expression of estrogen, progesterone and an epidermal growth factor receptor known as HER-2/neu, receptors that are targets for most breast cancer therapies, chemotherapy associated with significant side effects remains the only treatment option.
“Effective and less toxic treatments are desperately needed for triple-negative breast cancer, and City of Hope will continue to work toward finding more therapies for these patients,” Diamond said.
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