Trial of Immunotherapy for Metastatic Triple Negative Breast Cancer – Jennifer Specht, M.D.

 

About 15% of breast cancers do not express any of the three key proteins - Estrogen Receptor, Progesterone Receptor, and HER2 Receptor - for which we have effective targeted therapies. This subset is called “Triple Negative Breast Cancer,” or TNBC. Lacking therapeutic target receptors, chemotherapy is the main treatment option at this time for patients with TNBC.   TNBC is more often diagnosed in young women and is associated with a poorer prognosis than other types of breast cancer making development of new therapies an urgent, unmet need.

 

Cancer immunotherapy, which uses our immune system to help attack cancer cells, is an exciting area of cancer research with successes (and newly approved drugs) in several cancer types. To date, immunotherapy strategies have been difficult to develop in breast cancer, in large part due to the fact that most breast cancer cells appear very much like normal breast cells to our immune system. There are few unique targets on breast cancer cells that are not found on our normal tissues to which we can direct the immune system, and misdirected  immune responses to healthy cells can result in serious auto-immune diseases. 

 

In order to keep a balance that allows important immune infection-fighting functions to occur without harming normal body tissues, the immune system is carefully regulated, with proteins and cells that function to both stimulate and inhibit immune responses. Pembolizumab (Keytruda) is an antibody that has been developed to target an immune protein called the Programmed Cell Death 1 (PD-1) receptor. This receptor is responsible for inhibiting immune responses. Normally, this effect is necessary to avoid an inappropriate overreaction, such as auto-immune disease in healthy individuals. In patients with cancer, antibody blockade against this receptor, such as with pembrolizumab, can reinvigorate the immune system, allowing it to target and destroy cancer cells. Pembrolizumab is one of a number of therapies that are part of the “immune checkpoint blockade.” Pembrolizumab has recently been approved for the treatment of melanoma and lung cancer. A small study has shown tumor shrinkage in some triple negative breast cancer patients. As a result, trials using pembrolizumab in TNBC patients are in development.  

 

Dr. Jennifer Specht at the University of Washington/Seattle Cancer Care Alliance has developed an exciting clinical trial of pembrolizumab in combination with chemotherapy in patients with metastatic triple negative breast cancer. The additional funding from Wings of Karen will allow biopsies of metastatic cancer before and after treatment with pembrolizumab for studies of the tumor immune “microenvironment.” The results of the biopsies will be compared to findings on radiology exams that evaluate tumor metabolism and activity (FDG PET studies). The study will specifically look at subsets of T cells and macrophages, cells critical to the immune system, seen in the biopsy that are located within or near the tumor. It is known that in some TNBC there are immune cells that recognize and are located in the area of the cancer that are being suppressed from acting through the PD-1 receptor and other forms of immune blockade. Pembrolizumab could “unleash” the inhibition of these cancer-fighting immune cells. The study’s hypothesis is that the baseline pattern of immune cells in the tumor “microenvironment” will predict for response (or resistance) to pembrolizumab therapy. Evaluation of the tumor microenvironment before and after therapy with will provide important insights into the mechanism of action of immune checkpoint blockade drugs. Dr. Specht will be partnering with colleagues at the University of Washington, Fred Hutchinson Cancer Research Center, and Oregon Health Sciences University in this important trial that will lead to a better understanding of how to harness the immune system in fighting cancer.