City of Hope scientists have combined a checkpoint inhibitor with an anti-parasitic drug, ivermectin, to successfully treat triple-negative breast cancer in preclinical research, according to a study published March 2 in npj Breast Cancer journal. (Ivermectin is also currently being used in clinical trials to treat and prevent COVID-19.)
Triple-negative breast cancer is a difficult type of cancer to treat because the tumor cells lack three key proteins — receptors for the hormones estrogen and progesterone and the protein HER2. Doctors now treat breast cancer based on targeting these three key proteins, but without them, triple-negative breast cancer has limited treatment options.
Peter P. Lee, M.D., Billy and Audrey L. Wilder Professor in Cancer Immunotherapeutics, researchers found that by combining anti-PD1 monoclonal antibodies and ivermectin, triple-negative breast cancer could be treated.
First, ivermectin turned “cold tumors,” which have little to no T cells, or immune cells, into “hot tumors,” or tumors with a high number of T cells.
Turning the tumors into hot tumors then enabled anti-PD1 monoclonal antibodies to work. The checkpoint inhibitors blocked the PD1 protein, helping the immune system and, specifically, T cells, do what they’re designed to do: eradicate cancer.
“For the most part, checkpoint inhibitors have not worked in treating breast cancer,” Lee said. “This is the first time we can show that by adding an inexpensive, existing safe drug, you can make breast cancer treatable with immune checkpoint therapy. It’s the two drugs working together that is the magic. Either drug alone has almost zero effect, but together they have a powerful synergistic effect.”
Lee explained that cells may die in different ways. When cells die by apoptosis, they also silence the immune system. A recently identified phenomenon known as immunogenic cell death is a form of cell death that induces a T cell response against cancer cells.
Ivermectin killed cells by immunogenic cell death, thus triggering T cells — a finding that Lee’s lab also discovered previously using cancer cell lines and now, for this study, using animal models.
“While the cost of a single dose of anti-PD1 antibody therapy is roughly $15,000, ivermectin is roughly $30 per dose, making it truly accessible for everyone, including cancer patients in developing countries,” Lee added.
Since 1975, ivermectin has been used to treat close to 1 billion people, primarily for river blindness and other parasitic infections. In the last year, ivermectin has also demonstrated efficacy against COVID-19, and it is being tested in dozens of clinical trials to both prevent and treat the virus.
Forty to 60% of animals treated with the therapeutic combination completely eradicated their tumors and were able to fight off the cancer again after it was reintroduced.
Furthermore, Lee and his team also tested the combination across a spectrum of clinically relevant settings. A primary tumor refers to the tumor that started a cancer. They found that the therapeutic combination also worked in neoadjuvant models (those who received treatment before surgical removal of a primary tumor) and adjuvant models (after a primary tumor was surgically removed). The therapies even worked against metastatic breast cancer, or when the disease had spread beyond the primary tumor.
Next steps for the therapeutic combination include testing adequate dosing levels for a potential first-in-human clinical trial.
“These results have potential impact both on the basic biological understanding of immune checkpoint blockade therapy for breast cancer and rapid clinical translation, since both agents have already been approved by the Food and Drug Administration and have demonstrated safety in humans,” Lee said.