Scientists racing to understand why drugs worked for few patients
No one expected the four young women to live much longer. They had an extremely rare, aggressive and fatal form of ovarian cancer. There was no standard treatment.
The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionised treatment of cancer. At first, they were told the drugs were out of the question – they would not work against ovarian cancer.
Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.
The tale has befuddled scientists, who are struggling to understand why the drugs worked when they should not have. If researchers can figure out what happened here, they may open the door to new treatments for a variety of other cancers thought not to respond to immunotherapy.
“What we are seeing here is that we have not yet learned the whole story of what it takes for tumours to be recognised by the immune system,” says Dr. Jedd Wolchok, chief of the melanoma and immune-therapeutics service at Memorial Sloan Kettering Cancer Centre in New York. “We need to study the people who have a biology that goes against the conventional generalisations.”
Four women hardly constitutes a clinical trial. Still, “it is the exceptions that give you the best insights,” says Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.
The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman’s teens or 20s. It is so rare that most oncologists never see a single patient with it.
But Dr. Douglas Levine, director of gynaecologic oncology at New York University Langone Medical Centre, specialises in this disease. A few years ago, he discovered that the cancer was driven by a single gene mutation. The finding was of little use to patients – there was no drug on the horizon that could help.
Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.
The women reported that their tumours shrank immediately.
The idea behind immunotherapy is to dismantle a molecular shield that some tumours use to avoid an attack by the body’s white blood cells.
The immune system sees these tumours as foreign – they are fuelled by hundreds of genetic mutations, which drive their growth and are recognised by the body. But when white blood cells swarm in to attack the cancer cells, they bounce back, rebuffed.
Immunotherapy drugs pierce that protective shield, allowing the immune system to recognise and demolish tumour cells. But the new drugs do not work against many common cancers.
Those cancers are supported by fewer genetic mutations, and experts believe that the tumour cells just do not look threatening enough to the body to spur a response. So the immune system leaves them alone.
Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumours — carry few mutations.
“These are the cancers that rarely respond,” Pardoll says.
The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fuelled by just one genetic mutation, just made no sense.
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