By attaching a chemotherapy drug to an antibody, doctors are able to deliver more potent cancer-fighting medicines directly into tumor cells, all while causing fewer side effects.
The chemotherapy-antibody combinations, known as antibody drug conjugates, have been described as both heat-seeking missiles and Trojan horses for cancer cells, designed to specifically home in on a patient’s tumor cells and trick them into engulfing the antibodies, along with their deadly 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 cancers of the breast, lung, cervix and ovaries, and more than 100 are in clinical development, according to a review in the journal Cancers.
Oncologists, however, have become increasingly enthusiastic about the treatments in recent years, as researchers have pinpointed new, better targets that allow the drugs to take down cancer cells with more accuracy.
“There’s been an explosion of these agents over the past couple of years and we have a ton of them in clinical trials right now,” said Dr. Erika Hamilton, a medical oncologist and the director of breast cancer and gynecologic cancer research at Sarah Cannon Research Institute in Tennessee.
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 cancers progressing further.
“It’s really starting to come into its own,” Dr. Hatem Soliman, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, said of the research. “It appears to be here to stay.”
How it works
Roughly 2 million people in the U.S. will be diagnosed with cancer this year, according to the National Cancer Institute. Chemotherapy will be the standard treatment for many of those patients.
Chemotherapy drugs work by killing cancer cells. While often effective, they can also come with major side effects because they’re unable to discriminate between cancer cells and healthy ones.
Antibody drug conjugates, on the other hand, are designed to attack only cancer cells, thanks to the addition of specialized monoclonal antibodies that seek out specific targets on the cancer cells.
“It’s kind of like a Trojan horse,” said Dr. Giuseppe Curigliano, co-chair of the experimental therapeutics program at the European Institute of Oncology in Italy. “The antibody can bind specifically to a target region, and once there is the binding, you can bring the chemotherapy into the cancer cells.”
The approach also means that much more of the drug gets inside of the tumor cells.
“You’ve delivered chemo inside the cancer cell,” said Dr. Julie Gralow, ASCO’s chief medical officer and executive vice president. “You can get very high levels of chemo inside the cancer cell, levels that in many cases with these drugs you couldn’t achieve if you just gave the drug by itself into the vein.”
Delivering the drug directly into the cell allows doctors to use more potent forms of chemotherapy, including some that were previously found to be too toxic to patients.
These were drugs that “were really toxic to the tumor, but they were also really toxic to the patient,” Gralow said. “But now, you can put them on an antibody and you can deliver them in a way where you can still get a really high level in the cancer cell and lower level out in the rest of the body, and you can start using them.”
But this approach doesn’t eliminate side effects entirely, she added. Patients can still experience common chemotherapy side effects 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 that the cancer had come back and spread to her liver and bones.
When her cancer stopped responding to traditional chemotherapy, her oncologist, Soliman of Moffitt Cancer Center, explored the option of using an antibody drug conjugate.
The treatment, Soliman said, led to a major improvement in Fish’s disease, and she’s been in stable condition.
“She’s been 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 has been feeling great on the new treatment.
“I played, two weeks ago, 18 holes of golf, so it’s been pretty darn good,” she said.
‘A clear, clear positive signal’
Fish later learned that she had a subtype of breast cancer called HER2-low, a recently identified form of the disease.
Previously, breast cancers had been classified as being either 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 those 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 the length of time patients with HER2-low breast cancer went without their tumors getting worse by about five months compared to those who got chemotherapy.
“The study clearly demonstrated that trastuzumab is better than standard chemotherapy,” said senior author Curigliano, of the European Institute of Oncology, using the technical name for the treatment. “There is a dramatic impact on the lives of patients.”
In April, the Food and Drug Administration expanded Enhertu’s approval, saying the treatment could be used for any type of cancer with the HER2 molecule. The drug was already approved for breast and lung cancer, but now can 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 got pomalidomide and dexamethasone, two drugs often used together to treat multiple myeloma. Roughly half were also given Blenrep, and the other half got bortezomib, a drug that’s been shown to be successful in delaying progression of the disease and is approved in the U.S.
The researchers, led by Dr. Suzanne Trudel, a professor of medicine at the University of Toronto, found that after 12 months, 71% of the people who got the Blenrep combination therapy saw no progression of their cancer, compared to 51% of the patients in the other group.
After about 22 months, she said, more than half of the patients in the Blenrep group still hadn’t seen any progression. The 50% mark for progression was hit at 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 rocky history: It was granted fast-track approval by the FDA in 2020, but two years later, the agency asked GlaxoSmithKlein to pull the drug from the market after a phase 3 trial failed to show that it worked better than an existing treatment.
Gralow said the new findings could persuade the FDA to approve the drug once again.
A ‘warhead’ for cancer
The results add to excitement that the treatments could one day be the standard approach for chemotherapy, said Sophia Karagiannis, a translational cancer immunologist at King’s College London.
Karagiannis published a study in the journal Clinical Cancer Research in May that found researchers were able to use a tailor-made antibody drug conjugate for triple-negative breast cancer, one of the most difficult-to-treat forms of the disease.
“I would describe them as smart warheads,” she said. “I think the future will be that we will be able to combine chemotherapy with many of these smart drugs.”
The focus for many oncologists right now is figuring out how to make the drugs attack cancer cells more precisely as well as making the effects last longer.
“ADCs are in some ways more complicated than chemotherapies in that they are more complex molecules, they’re bigger,” Karagiannis said. “We are trying to understand how well we can make those molecules so that they can be more stable.”
Dr. Dale Shepard, a medical oncologist with the Cleveland Clinic, said because the treatments are so effective at attacking cancer cells, patients often report fewer side effects and also have to come to get their infusions less often — about once every 28 days versus every one or two weeks with traditional chemotherapy.
The treatments are often more expensive than traditional chemotherapy, however.
Hamilton, of the Sarah Cannon Research Institute, said that some antibody drug conjugates are already being widely used, even as a first-line chemotherapy treatment, as opposed to waiting until after traditional chemotherapy isn’t successful.
“Getting these drugs to patients earlier is already underway,” Hamilton said. “They are for sure going to have a firm role in oncology.”
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