Checkpoint Inhibitors Boost Power of Antibody–Drug Conjugate

When it comes to treating HER2-positive breast tumors, antibody–drug conjugates (ADC) and checkpoint inhibitors may be more potent together than either type of drug alone, a recent study shows. The results suggest that combining the drugs could make them effective against other cancers as well.

An ADC consists of a cell-killing compound fastened to a monoclonal antibody. The antibody delivers the drug to the tumor, increasing its effectiveness while reducing side effects. One example is T-DM1 (ado trastuzumab emtansine, or Kadcyla; Genentech). It pairs trastuzumab (Herceptin; Genentech) with the microtubule-disrupting molecule DM1 and was approved in 2013 as a second-line treatment for HER2-positive metastatic breast cancer.

In previous research, Philipp Müller, PhD, and Alfred Zippelius, MD, of the University of Basel in Switzerland, and colleagues found that ADCs do more than poison tumor cells. They reported in 2014 that a precursor of DM1 spurs dendritic cells to mature and stimulates antitumor immunity, leading them to hypothesize that some of T-DM1′s benefits might stem from these effects.

To test that hypothesis, the researchers analyzed biopsies of HER2-positive breast tumors from 28 women in the WSG-ADAPT clinical trial. After 3 weeks of therapy with T-DM1, the number of lymphocytes in the tumors surged, indicating that the ADC promotes T-cell infiltration in patients with breast cancer.

The researchers also explored this effect in mice with implanted breast tumors that overexpressed HER2. The 65 untreated mice died within 25 days. However, one dose of T-DM1 nearly doubled survival in another group of animals, and 25% to 35% of mice that received two T-DM1 treatments were alive and tumor-free 175 days after the experiment began.

T cells and macrophages from treated mouse tumors showed increased expression of the checkpoint proteins CTLA-4, PD-1, and PD-L1, indicating that the tumors were inhibiting the infiltrating lymphocytes. The researchers wondered if they could counteract this suppression by adding checkpoint inhibitors that block CTLA-4 and PD-1. Mice treated with only checkpoint inhibitors didn't survive longer than controls. However, 95% of the mice that received checkpoint inhibitors and T-DM1 were alive and free of tumors after 175 days, the team reported last month in Science Translational Medicine. These mice also retained an immunologic memory, quickly destroying new implanted tumors.

Some studies suggest that checkpoint inhibitors are effective in triple-negative breast cancer, and in the new trial “we may have evidence of checkpoint inhibitors producing a benefit in HER2-positive tumors,” says Sasha Stanton, MD, PhD, of the University of Washington in Seattle, who wasn't connected to the research.

Checkpoint inhibitors and ADCs might also work for other tumor types that overexpress HER2, including some esophageal and gastric cancers, she says.

“The authors should be applauded for the detail and thoughtfulness of their experiments,” adds Kimberly Blackwell, MD, of the Duke University School of Medicine in Durham, NC. She cautions, however, that the results don't show whether the benefits the researchers detected stem from T-DM1, trastuzumab, or DM1—an important consideration when deciding which drug combinations to test in patients. –Mitch Leslie