Targeting Breast Cancer with more Punch

To optimize current treatment and develop methods to more efficiently treat breast cancer, scientists have been researching molecules that selectively bind to cancer cells and deliver a specific, targeted, drugs that can kill the tumor cells. Now, for the first time, researchers from the University and University Hospital Basel have successfully combined such an antibody-drug conjugate with a therapy that stimulates the immune system to attack tumor cells.  Antibody-drug conjugates have emerged as a powerful strategy for cancer therapy.

Results from a new study, opening the door to new therapeutic options in the treatment of breast cancer, was reported by researchers in the scientific journal Science Translational Medicine. [1]

Targeting breast cancer
In nearly every fifth breast cancer patient, an above-average number of the human epidermal growth factor receptor 2, also known as HER2 receptors, are located on the surface of the tumor cells.  In these cases, patients have a gene mutation that makes an excess of the HER2-protein. The HER2 receptors receptors are molecules that send growth factor signals into the cell. The overabundance of receptors causes the cancer cells to divide rapidly and the tumor grows faster than average.

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The overexpression of HER2 is associated with poor outcomes and despite the availability HER2-targeted agents. The primary reason for this poor outcomes is that many patients develop resistance to the targeted drugs

Antibody-drug conjugates
For some years now, a new class of drugs called antibody-drug conjugates or ADCs have been used, which work in two ways: they consist of an antibody that binds selectively to the tumor cell receptor and interrupts the signal to propagate; they also act as a transport vehicle for a chemical substance that enters the cancer cells with the antibody and triggers their death. The researchers demonstrate that the use of specific cytotoxic substances can also have a beneficial effect on the body’s immune system.

Photo 1.0 – Alfred Zippelius, MD, is Full Professor of Translational Oncology, Laboratory of Cancer Immunology & Biology, Department Biomedicine, University and University Hospital Basel, in Basel, Switzerland. Courtesy: © University and University Hospital Basel, in Basel, Switzerland. Used with permission.

Combination with immunotherapy
Researchers, led by Professor Alfred Zippelius at the Department of Biomedicine, from the University and University Hospital Basel, in Basel, Switzerland, have now gone one step further: in a pre-clinical study performed in mouse breast cancer models, they combined ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), a treatment for HER2-positive metastatic breast cancer, with an additional immunotherapy that activates the immune system into attacking tumors more efficiently.

Immune checkpoint inhibitors
In their research, the scientists focused on what is known as immunoregulatory checkpoints. These are receptors on immune cells, which control for example effector T-cells by dampening their activation if damage to healthy cells is imminent. By administering a complementary antibody, they blocked the function of two such immune checkpoints, whereby different types of endogenous T-cells were activated.

On its own, this immune response had no immediate effect in the fight against the utilized breast tumors, but in combination with the antibody-drug conjugate it proved itself effective in attacking cancer cells in mice, resulting in the complete cure of the majority of mice receiving the combination therapy. The researchers were also able to further demonstrate that regulatory T-cells play a host protective role in this therapeutic setting. Their removal resulted in excessive inflammation and tissue damage.

Clinical Trials
Results from the German phase II ADAPT study, showed that neoadjuvant ado-trastuzumab emtansine is effective in the treatment of HER2-positive, hormone receptor (HR)-positive breast cancer, with or without endocrine therapy. The trial compared this therapy with the treatment of trastuzumab (Herceptin®; Genetech/Roche) and endocrine therapy.[2][3]

The results of an interim analysis of the ADAPT study were presented by the researchers during the 51 Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 29 – June 2, 2015 in Chicago, Illinois (ASCO, abstract 506).[4]

“We’ve  showed that that ado-trastuzumab emtansine is particularly effective in eliciting antitumor immunity in patients with early breast cancer and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, we combined treatment with ado-trastuzumab emtansine and anti–CTLA-4/PD-1 (cytotoxic T lymphocyte–associated protein-4/programmed cell death protein-1). The result was curative because it triggered innate and adaptive immunity,” Zippelius explained.

Significance
Ongoing trials have shown that poor outcomes as a result to the development of resistance can be overcome with ado-trastuzumab emtansine. In addition to its cytotoxic effects, this treatment activates a strong antitumor immune response and when effectively combined with immune checkpoint inhibitors may successfully be used in a combination therapy.

“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,” noted Philipp Müller, MD, head of the cancer immunology and immunotherapy laboratory at the department of biomedicine at the University & University Hospital of Basel, Switzerland, the lead author f the paper, emphasizing the significance of the study.

This new combination therapy is expected to create effective targeted therapies with more punch.