After giving up on cancer vaccines, doctors see hope

It seems like an almost impossible dream — a cancer vaccine that would protect healthy people at high risk of the disease. Any incipient malignant cells would be eliminated by the immune system. It would be no different from how vaccines protect against infectious diseases.

However, unlike the latter, the promise of a cancer immunizer has frustrated researchers in the past, despite their strenuous efforts. Now, however, many hope that some success may be at hand in the quest to protect people from cancer.

The first vaccine involves individuals with a high chance of developing pancreatic cancer, one of the most difficult to treat when it is evolving. Other vaccine studies involve people at high risk of colon and breast cancer.

Of course, this research is in its early days, and vaccine efforts could fail. But the animal data are encouraging, as are some preliminary studies in human patients, and the researchers demonstrate new optimism.

“There’s no reason why cancer vaccines can’t work if given at an early stage,” said Sachet Shukla, who directs a cancer vaccine program at the MD Anderson Cancer Center in Texas. “Cancer vaccines,” he added, “are an idea whose time has come” (Shukla owns shares in companies that develop cancer vaccines).

That view is a far cry from where this field was a decade ago, when researchers almost gave up. Studies that would have seemed like an impossible dream are under way.

“People would say it’s crazy,” said Susan Domchek, principal investigator of a breast cancer vaccine trial at the University of Pennsylvania.

Now, she and others predict a time when anyone with a precancerous condition or genetic predisposition to the disease can be vaccinated and protected.

“It’s super aspirational, but we need to think big,” Domchek said.

less bleak prognosis

Marilynn Duker knew that her family tree included several relatives who had cancer. So when a genetic counselor offered her the test to see if she had any of the 30 cancer-causing gene mutations, she readily accepted.

The test found a mutation in the CDKN2A gene, which predisposes people who have it to pancreatic cancer.

“They called and said, ‘You have this mutation. There’s really nothing you can do,'” recalled Duker, who lives in Pikesville, Maryland, and is CEO of a senior housing company.

She began having regular scans and endoscopies to examine her pancreas. They revealed a cyst. It hasn’t changed in recent years. But if it develops into cancer, treatment will likely fail.

Patients like Duker don’t have many options, said Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. A person with more advanced cysts could stave off cancer by removing the pancreas, but that would immediately plunge them into a realm of severe diabetes and digestive problems. Drastic surgery can be worth it if it saves a life, but many precancerous lesions never turn into cancer if they are simply left alone. However, if the lesions turn into cancer – even if it is detected at an early stage – the prognosis is grim.

The situation offers an opportunity to make and test a vaccine, she added.

In pancreatic cancer, Jaffee explained, the first shift in normal cells toward malignancy is almost always a mutation in a known cancer gene, KRAS. Other mutations follow, with six of them causing pancreatic cancer to grow in most patients. This insight allowed the Hopkins researchers to develop a vaccine that would train T cells — the immune system’s white blood cells — to recognize cells with these mutations and kill them.

Its first trial, a safety study, was in 12 patients with early-stage pancreatic cancer who had already been treated with surgery. Although in these cases the cancer was detected soon after it appeared, and despite the fact that they were treated, patients with pancreatic cancer typically have a 70% to 80% chance of having a recurrence in the following years. When pancreatic cancer returns, it is metastatic and fatal.

Two years later, these patients still have not had a recurrence.

Now Duker and another patient have been vaccinated to try to prevent a tumor from starting. “I’m really excited about this opportunity,” she said.

The vaccine appears safe and has provoked an immune response against mutations common in this cancer.

“So far so good,” Jaffee said.

But only time will tell if it prevents cancer.

Blocking a precursor

Mary Disis, director of the University of Washington Cancer Vaccine Institute, wants to prevent breast cancer in women with genetic variants that put them at high risk. His initial hopes, however, are more modest.

One goal is to help women who have ductal carcinoma “in situ,” which doctors call pre-cancer. Surgery is the standard treatment, but some women also have chemotherapy and radiation to protect themselves from developing invasive breast cancer. “Ideally, a vaccine would replace these treatments,” she said.

Disis began by examining breast cancer stem cells, which are found in early cancers. These cells are resistant to chemotherapy and radiation and can metastasize. They cause breast cancer recurrences, said Disis, who has received grants from pharmaceutical companies and is the founder of EpiThany, a company that is developing vaccines.

She and her colleagues found several proteins in these stem cells that were normal but produced at a much higher level in cancer cells than in non-cancerous ones. This offered an opportunity to test a vaccine that produced some of these proteins.

The vaccine was tested in women with well-established advanced cancer. It didn’t cure cancers, but it did demonstrate that the vaccine can provide the kind of immune response that can help get the disease started.

Disis plans to vaccinate patients with ductal carcinoma “in situ” or another precancerous condition, atypical ductal hyperplasia. His group has a vaccine designed to target three proteins produced in abnormally high amounts in these lesions.

The hope, she said, is to make the lesions lessen or disappear before women have surgery to remove them.

“It would be proof that the vaccine has a cleaning effect,” she said. If the vaccine is successful, women may feel safe to forgo chemotherapy or surgery.

a great future

“I really think we’re going to see some clinically approved vaccines in the next five years,” Disis said. The first vaccines, she predicts, will be used to prevent recurrences in patients whose cancer has been successfully treated.

“So I think we’re going to move very quickly to primary prevention,” vaccinating healthy people at high risk, she said.

Others are equally optimistic.

“At least we know the roadmap,” said Shizuko Sei, a physician with the National Cancer Institute’s chemopreventive agent development research group.

“People may disagree, but the answer right now is yes, it is possible” to make vaccines to intercept cancer, she said.

Domchek said he could envision a future where people will get blood tests to find cancer cells so early that they won’t show up on imaging tests or standard tests.

“To paint a great future,” she said, “if we knew tests would predict cancer, we could say, ‘Here’s your vaccine.'”