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 immunotherapeutics 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.

“For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load,” Pardoll explains.

But there were a few oddball exceptions. An unusual skin cancer called Merkel cell carcinoma responded to immunotherapy, scientists found. It is caused by a virus, and researchers suggest the infection itself draws the attention of the immune system.

Mesothelioma also responds, perhaps because the asbestos that causes it also inflames the immune system. And some kidney cancers respond to immunotherapy treatment; no one knows why.

And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, is one of them.

She found out she had cancer in December 2011. She knew something was wrong – for several months she had been feeling tired, constipated and endlessly thirsty. She began vomiting and had abdominal cramps. But her doctors told her she was fine and not to worry.

Finally, her aunt, a nurse, suggested she see a different doctor, who performed a CT scan of her abdomen. It revealed a huge mass. The doctor operated to find out what it was. Two days later, he gave her the bad news: cancer, and a terrible form of it.

For the next four years, Sousa’s doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumours emerged.

“I suffered a lot, and I felt I had no life,” she says.

Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumours shrank and continued shrinking as she continued with the drug – so much that her doctors now say she has no evidence of disease. Life has returned to normal.

“Generally after work, I go to the gym and do classes and work out,” she says. “People who don’t know what I have been through, they can’t imagine I am an oncology patient.”

What saved her? Dr Eliezer M Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.

He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognise as abnormal.

Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. “We saw this result and weren’t sure what to make of it,” he says.

Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Van Allen say, is that the immune system may recognise that cells in which genes are erratically turning on and off are dangerous and should be destroyed.

“That is strictly hypothesis,” Levine cautions.

One thing is clear, though: when pathologists examine these tumours, they find white blood cells in them – as if the immune system is trying to attack. And that finding has led both Pardoll and Dr Padmanee Sharma of MD Anderson Cancer Centre in Houston to plan new clinical trials.

They know that immunotherapy fails most patients, even those with cancers that are most likely to respond. So they have set out to create a test to determine who might respond to immunotherapy and then treat those patients – regardless of their cancer type.

Sharma’s study, funded by the Parker Institute, is getting ready to enrol patients. The researchers will look at pathology slides of patients’ tumours to see if white blood cells are worming their way into the cancers. If so, the patients will get an immunotherapy drug to help activate their white blood cells to attack the tumour.

If there are few white blood cells in the tumour tissue, patients will get a combination of two immunotherapy drugs to help move more white blood cells into the tumour and help them attack.

“The trial is written for all comers,” Sharma says. “If we have learned anything, it is that it is not the tumour type we are treating – it is the immune system.”

At Johns Hopkins, Pardoll and his colleagues are planning a similar trial. They will be looking for tumours – it does not matter what type – that have a protein, PD-1, on the surface that repels the immune system. Any patient whose tumour fits that description will get an immunotherapy drug.

It’s a shot in the dark. But sometimes such a shot finds the mark, as Sousa will tell you.

“Incredible things happen, and against all the odds,” she says.