February 18, 2014
Researchers find new potential drug target in triple-negative breast cancer
BY MD Anderson Staff
The goal of harnessing the power of one's immune system to target and kill cancer cells just got a boost. New research from MD Anderson has yielded promising insights into a protein known as PDL1, which was found to be expressed in 20% of triple negative breast tumors.
Triple-negative disease is more aggressive than other types of breast cancer and is not fueled by female hormones estrogen and progesterone or by the cancer growth-promoting protein HER2. Thus, it does not respond to established hormone and HER2 therapy and is more difficult to treat.
The findings of the study led by Elizabeth Mittendorf, M.D., Ph.D., professor of Surgical Oncology, were recently published in Cancer Immunology and Research, a journal of the American Association for Cancer Research.
Mittendorf and her colleagues were interested in whether or not PDL1 was expressed in breast tumors because its presence might be the reason T-cells, our body's natural defense mechanism, are unable to destroy rogue cancer cells in this environment. Unlocking this clue could open the door for a new target or treatment strategy.
In the accompanying video, Mittendorf discusses the findings and their clinical implications, including clinical trials and possible enhancement of therapeutic vaccines, in greater detail. Mittendorf has developed a therapeutic vaccine that targets breast cancer cells bearing the HER2 protein that is progressing in clinical trials.
PDL1 flips an off switch on T cells
PDL1 activates a receptor on the surface of T cells called PD1 that shuts down immune response. This immune checkpoint mechanism usually protects normal cells from immune system attack but is hijacked by cancer cells to protect themselves.
An MD Anderson clinical trial for a variety of cancers, including triple-negative breast cancer, combines an experimental drug that blocks PD1 with an established drug called ipilimumab (Yervoy) that blocks a different immune checkpoint on T cells. Other drugs are under development to hinder PD1 and PDL1.
Mittendorf noted there's great interest in validating these preclinical findings in larger, well-designed trials as a next step. Researchers will also need to examine the tumor microenvironment, to determine how other cells may effect PDL1 expression.
The field of immune checkpoint blockade was opened by Jim Allison, Ph.D., now chair of Immunology and executive director of the immunotherapy platform for MD Anderson's Moon Shots Program.
Immunotherapy at MD Anderson
Allison identified the CTLA-4 checkpoint on T cells and developed an antibody to block CTLA-4 that became the drug ipilimumab, the first ever to extend survival for late-stage melanoma patients. So far, more than 20 percent of patients who received ipilimumab have survived for up to 12 years and counting.
Since his recruitment in late 2012, Allison has expanded and enhanced MD Anderson's capabilities in immunotherapy expertise, technology and techniques. Clinical trials at MD Anderson of checkpoint blockade drugs also target lymphoma, lung, gastric and prostate cancers, with more to come.
In December, the journal Science named cancer immunotherapy its breakthrough of the year. Read on for more information on that designation, immunotherapy and MD Anderson efforts.