Antibody-drug Conjugates Show Potential in Breast Cancer

Researchers have successfully combined an antibody-drug conjugate (ADC) with a therapy that stimulates the immune system to attack tumor cells. This breakthrough opens the door to new therapeutic options in the treatment of breast cancer, according to studies conducted in a mouse model and reported in Science Translational Medicine (doi: 10.1126/scitranslmed.aac4925 ).

In approximately 20% of patients with breast cancer, an above-average number of HER2 receptors are located on the surface of tumor cells, which can cause cancer cells to divide rapidly, resulting in faster-than-average growth of the tumor.

The ADC class of drugs works in 2 ways. While the antibody binds selectively to the tumor cell receptor and interrupts the signal to propagate, the drug also acts as a transport vehicle for a chemical substance that enters the cancer cells with the antibody and triggers apoptosis.

This study—led by Professor Alfred Zippelius, MD, at the Department of Biomedicine, University Hospital Basel, Switzerland—demonstrates that specific cytotoxic substances can have a beneficial effect on the body's immune system. This preclinical research in mouse models of breast cancer involved combining the ADC trastuzumab emtansine with an additional immunotherapy that activates the immune system into attacking tumors more efficiently.

The researchers focused on immunoregulatory checkpoints, which are receptors on immune cells that control signals, such as that of effector T cells. These checkpoints dampen the activation of effector T cells if damage to healthy cells is imminent. By administering a complementary antibody, the investigators impeded the function of 2 such immune checkpoints, whereby different types of endogenous T cells were activated.

Although this immune response had no independent immediate effect against the breast tumors studied, combination with the ADC resulted in an immune response that was effective in attacking cancer cells in mice, resulting in the complete cure of most of the mice receiving the combination therapy. The researchers were also able to demonstrate that regulatory T cells are protective in this therapeutic setting as their removal resulted in excessive inflammation and tissue damage.

"Our results clearly demonstrate that antibody-drug conjugates are suitable for use in a combination therapy, opening new perspectives for the treatment of breast cancer," said lead author Philipp Müller, PhD.

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