Anti-cancer antibodies inject chemotherapy directly into tumor cells, increasing effectiveness

By attaching a chemotherapy drug to an antibody, doctors are able to deliver more powerful cancer drugs directly into tumor cells, while causing fewer side effects.

Chemotherapy-antibody combinations, known as antibody-drug conjugates, have been described as both heat-seeking missiles and cancer cell Trojan horses, designed to specifically target a patient’s tumor cells and trick them into engulfing the antibodies, along with their deadly effects. payload.

The approach isn’t entirely new: The first antibody-drug conjugate was approved by the Food and Drug Administration in 2000 to treat acute myeloid leukemia, a type of blood cancer. Since then, other approvals have followed, for treatments targeting breast, lung, cervical and ovarian cancers, and more than 100 are in clinical development, according to a review in the journal Cancers.

Oncologists, however, have become increasingly enthusiastic about these treatments in recent years, as researchers have identified new, more effective targets that allow the drugs to kill cancer cells more precisely.

“There has been an explosion of these agents over the last couple of years and we have a ton of them in clinical trials right now,” said Dr. Erika Hamilton, medical oncologist and director of cancer research. breast and gynecological cancer to Sarah Cannon. Tennessee Research Institute.

New research on two different antibody-drug conjugates, presented Sunday at the American Society of Clinical Oncology (ASCO) conference in Chicago, found that the treatments helped patients with multiple myeloma and breast cancer live longer without their cancer progressing further.

“This is really starting to make sense,” Dr. Hatem Soliman, a medical oncologist at Moffitt Cancer Center in Tampa, Fla., said of the research. “It looks like it’s here to stay.”

How it works

About 2 million people in the United States will be diagnosed with cancer this year, according to the National Cancer Institute. Chemotherapy will be the standard treatment for many of these patients.

Chemotherapy drugs work by killing cancer cells. Although they are often effective, they can also cause major side effects because they are unable to distinguish between cancer cells and healthy cells.

Antibody-drug conjugates, on the other hand, are designed to attack only cancer cells, through the addition of specialized monoclonal antibodies that seek out specific targets on cancer cells.

“It’s a bit like a Trojan horse,” said Dr. Giuseppe Curigliano, co-chair of the experimental therapy program at the European Institute of Oncology in Italy. “The antibody can bind specifically to a target region, and once binding is established, you can introduce chemotherapy into the cancer cells.”

This approach also means that more of the drug enters the tumor cells.

“You delivered chemotherapy inside the cancer cell,” said Dr. Julie Gralow, ASCO’s chief medical officer and executive vice president. “You can get very high levels of chemotherapy inside the cancer cell, levels that in many cases with these drugs you wouldn’t be able to achieve if you just gave the drug alone into the vein. »

Delivering the drug directly into the cell allows doctors to use more powerful forms of chemotherapy, including some that previously proved too toxic for patients.

These were drugs that “were really toxic to the tumor, but they were also very toxic to the patient,” Gralow said. “But now you can put them on an antibody and you can administer them in a way where you can still get a very high level in the cancer cell and a lower level in the rest of the body, and you can start to to use. »

But this approach doesn’t entirely eliminate side effects, she added. Patients may still experience common side effects of chemotherapy, including hair loss and low white blood cell counts.

For Rose Fish, 79, of The Villages, Florida, the side effects were more manageable than with standard chemotherapy, including less vomiting and hair loss.

Fish was diagnosed with breast cancer in 2011. After surgery, chemotherapy and radiation, she was cancer-free until 2020, when she learned the cancer had returned and spread to her liver and his bones.

When his cancer stopped responding to traditional chemotherapy, his oncologist, Soliman at Moffitt Cancer Center, explored the possibility of using an antibody-drug conjugate.

The treatment, Soliman said, has led to major improvement in Fish’s disease and his condition is stable.

“She is a good example of how ADCs are really changing the way we treat breast cancer and other diseases,” he said, using an abbreviation for antibody-drug conjugates.

Fish said she feels great thanks to the new treatment.

“Two weeks ago I played 18 holes of golf, so it went really well,” she said.

“A clear and clear positive signal”

Fish later learned she had a subtype of breast cancer called HER2-low, a recently identified form of the disease.

Previously, breast cancers were classified as HER2-positive or HER2-negative, depending on whether their tumor cells carried the HER2 molecule. However, up to 60% of breast cancers have low levels of the molecule, including about half of advanced breast cancers.

One of the studies presented Sunday at the ASCO conference found that Enhertu, an antibody-drug conjugate from drugmakers AstraZeneca and Daiichi Sankyo, extended by about five months the time breast cancer patients HER2-low were without worsening of their tumors. to those who received chemotherapy.

“The study clearly demonstrated that trastuzumab is better than standard chemotherapy,” said lead author Curigliano, of the European Institute of Oncology, using the treatment’s technical name. “There is a dramatic impact on patients’ lives. »

In April, the Food and Drug Administration expanded approval of Enhertu, saying the treatment could be used for any type of cancer with the HER2 molecule. The drug has already been approved for breast and lung cancer, but can now be used for cancers including stomach and colon, which can carry HER2.

Results from another study compared the antibody-drug conjugate Blenrep, from GlaxoSmithKline, to a more common treatment regimen for multiple myeloma.

The phase 3 clinical trial included more than 300 patients, all of whom received pomalidomide and dexamethasone, two drugs often used together to treat multiple myeloma. About half also received Blenrep and the other half received bortezomib, a drug that has been shown to delay disease progression and is approved in the United States

The researchers, led by Dr. Suzanne Trudel, professor of medicine at the University of Toronto, found that after 12 months, 71% of people who received the Blenrep combination therapy saw no progression of their cancer, compared to 51% of people who received Blenrep combination therapy. patients in the other group.

After about 22 months, she said, more than half of the patients in the Blenrep group still had seen no progression. The 50% progression mark was reached around 13 months in the other group.

“A clear, clear positive signal,” Trudel said. “I think this is really encouraging for patients with myeloma, which is an incurable disease.”

Blenrep has had a short but checkered history: It won accelerated approval from the FDA in 2020, but two years later the agency asked GlaxoSmithKlein to remove the drug from the market after a phase 3 trial failed. failed to show that it worked better. than an existing treatment.

Gralow said the new findings could persuade the FDA to re-approve the drug.

A “warhead” against cancer

The findings add to excitement that these treatments could one day become the standard approach for chemotherapy, said Sophia Karagiannis, a translational cancer immunologist at King’s College London.

Karagiannis published a study in May in the journal Clinical Cancer Research that found researchers were able to use a tailor-made antibody-drug conjugate for triple-negative breast cancer, one of the most challenging forms of the disease treat.

“I would describe them as intelligent warheads,” she said. “I think the future will be one where we can combine chemotherapy with many of these smart drugs. »

Currently, many oncologists are focusing on how to make drugs attack cancer cells more precisely and make their effects last longer.

“ADCs are, in some ways, more complicated than chemotherapies in that they are more complex and larger molecules,” Karagiannis said. “We are trying to understand to what extent we can make these molecules so that they are more stable.”

Dr. Dale Shepard, a medical oncologist at the Cleveland Clinic, said because treatments are so effective at attacking cancer cells, patients often report fewer side effects and also have to come in to receive their infusions less often — about once every 28 days versus every day. one or two weeks with traditional chemotherapy.

However, the treatments are often more expensive than traditional chemotherapy.

Hamilton, of the Sarah Cannon Research Institute, said some antibody-drug conjugates are already widely used, even as first-line chemotherapy treatments, instead of waiting until traditional chemotherapy fails.

“Getting these medications to patients sooner is already underway,” Hamilton said. “They will certainly play an important role in oncology.”