It seems like an almost impossible dream: a cancer vaccine that protect healthy people at high risk of suffering from it. Any incipient malignant cells would be eliminated by the immune system. It would be no different than the way vaccines protect against infectious diseases.
However, unlike infectious disease vaccines, the promise of cancer vaccines has been left to researchers alone, despite their arduous efforts. Now, however, many are hoping that some success in cancer immunization research is near.
The first vaccine is given to people with a very high probability of development pancreatic cancer, one of the most difficult cancers to cure once it is underway. Other vaccine studies involve people at high risk of colon and breast cancer.
Of course, these investigations are in its beginnings and vaccine efforts may fail. But the animal data is encouraging, as are some preliminary studies in human patients, and the researchers are filled with new optimism.
“There’s no reason cancer vaccines shouldn’t work if they’re given early,” said Sachet Shukla, who heads a cancer vaccine program at 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.)
This view is a far cry from the state of the research field ten years ago, when researchers almost gave up. Studies are underway that would have seemed like a pipe dream.
“People would have said it’s crazy,” says Susan Domchek, principal investigator of a breast cancer vaccine study at the University of Pennsylvania.
Now, she and others envision a time when anyone with a precancerous condition or genetic predisposition to cancer can be vaccinated and protected.
“It’s a great aspiration, but you have to think big,” says Domchek.
Less bleak prognosis
Marilynn Duker knew that her family tree was dotted with relatives with cancer. So when a genetic counselor offered her a test to see if she had one of her 30 cancer-causing genetic mutations, she jumped at the chance.
The test found a mutation in the CDKN2A genewhich predisposes people who lead to pancreatic cancer.
“They called me and said, ‘You have this mutation. There’s nothing I can do,'” recalls Duker, who lives in Pikesville, Maryland and is the CEO of a senior real estate company.
He began having regular scans and endoscopies to examine his pancreas. The results revealed the existence of a cyst. It hasn’t changed in the last few years. But if she turns into cancer, treatment is likely to fail.
Patients like Duker don’t have many options, said Dr. Elizabeth Jaffee, assistant director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.
A person with more advanced cysts may be able to avoid cancer by removing the pancreas, but that would immediately plunge them into a realm of severe diabetes and digestive problems. Drastic surgery might be worth it if it saved their lives, but many precancerous lesions don’t turn into cancer if left alone. However, if the lesions turn into cancer, even if the cancer is detected at an early stage, the prognosis is bleak.
But it also offers the opportunity to manufacture and test a vaccine, he added.
In pancreatic cancer, Jaffee explained, the first change in normal cells on the path to malignancy is almost always a mutation in a known cancer gene, KRAS. Other mutations follow, with six driving pancreatic cancer growth in most patients. This idea allowed Hopkins researchers to devise a vaccine that would train T lymphocytes (white blood cells of the immune system) to recognize cells with these mutations and kill them.
Their first study, a safety study, involved 12 patients with early-stage pancreatic cancer who had already been treated with surgery. Although the cancer was detected soon after it appeared and was treated, pancreatic cancer patients usually have it Between 70% and 80% chance suffer a relapse in subsequent years. When pancreatic cancer returns, it is metastatic and deadly.
Two years later, those patients still haven’t had a relapse.
Now, Duker and another patient have been vaccinated to try to prevent the cancer from starting.
“I am very excited about this opportunity,” he said.
The vaccine appears safe and has elicited an immune response against common mutations in this cancer.
“So far so good,” Jaffee said.
But only time will tell if it prevents cancer.
We have to look at several patients
In a way, the cancer vaccine research began with Olivera Finn, a professor in the immunology and surgery departments at the University of Pittsburgh School of Medicine.
It started in 1993 with a vaccine that targeted the nucleus of one molecule, muc1. In normal cells, the molecule is invisible to the immune system because it is covered with a number of sugar molecules. But in colon, breast and pancreatic cancers, it can become visible to the immune system. This made it seem like a perfect target for a vaccine, as it could allow the immune system to attack only cancer cells.
“We had this study, 63 patients, stage 4 cancer. All therapies had failed,” Finn explained.
The first patient had had breast cancer and was treated with a double mastectomy. But the cancer has returned.
“The tumor was in his chest, thick and red,” he said. “She had two pumps, one that emptied fluid from the lungs and one from the abdomen.”
In their initial studies, Finn and his colleagues became clear that the tumors were too advanced for the vaccinations to work. After all, he points out, with the exception of rabies, no one vaccinates against an infectious disease in people already infected.
“I said, ‘I don’t want to do it again,'” Finn said. “It’s not the vaccines. We have to look at the other patients.”
Now she and her Pittsburgh colleague Robert Schoen, a gastroenterologist, are trying to do it prevent precancerous colon polyps with a vaccine. But catching cancer can be tricky.
They focused on people whose colonoscopies had detected advanced polyps, nodules that can grow in the colon but only a minority of which turn into cancer. The goal, according to Schoen, was for the vaccine to stimulate the immune system to prevent new polyps.
It worked on mice.
“I said, ‘Okay, that’s great,'” Schoen recalls.
But a recently completed study of 102 people in six medical centers randomly assigned to receive the preventive vaccine or a placebo had a different result. They all had advanced colon polyps, giving them a three times greater risk of developing cancer in the next 15 years than people without polyps.
To separate a quarter of the vaccinated developed an immune response and there was a significant reduction in the polyp recurrence rate in the vaccinated group.
“We have to work to get a better vaccine,” Schoen said.
Preventing a precancer
Mary Disis, director of the University of Washington’s 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 of its goals is to help women who have DCIS, which doctors refer to as pre-cancer. Surgery is standard treatment, but some women also undergo chemotherapy and radiation to protect themselves from developing invasive breast cancer. “Ideally, a vaccine would replace these treatments,” she says.
He started by studying breast cancer stem cells. These cells, present in early cancers, are resistant to chemotherapy and radiation and can metastasize. They are the driving force behind breast cancer relapses, explains Disis, who has received grants from pharmaceutical companies and is the founder of EpiThany, a company that develops vaccines.
Disis and his colleagues discovered a number of proteins in these stem cells that were normal but were produced at a much higher level in cancer cells than in non-cancerous cells. Which offered the opportunity test a vaccine that produced some of those proteins.
The vaccine was tested on women with advanced cancers that were well established. It didn’t cure the tumors, but it did show that the vaccine could deliver the kind of immune response that could help early stages of the disease.
Disis plans to try to vaccinate patients with ductal carcinoma in situ or another precancerous disease, atypical ductal hyperplasia. His team developed a vaccine to attack three proteins produced in abnormally high quantities in these lesions.
The hope, she said, is for the lesions to shrink or disappear before the women have surgery to remove them.
“This would be proof that the vaccine has a purifying effect,” he said. If the vaccine is successful, women may feel comfortable giving up chemotherapy or surgery.
Painting a great future “I really think we will see some vaccines approved for the clinic over the next five yearsDisis said the first vaccines, he predicts, will be used to prevent recurrence in patients whose cancer has been successfully treated.
“Then I think we will move to primary prevention very quickly,” by giving vaccines to healthy people at high risk, he said.
Others are equally optimistic.
“At least we know the roadmap,” said Shizuko Sei, medical director of the research group on the development of chemopreventive agents at the National Cancer Institute.
“People may disagree, but the answer right now is yes, it is possible” to produce vaccines to intercept cancer, he said.
Domchek said he can envision a future where people will be subjected to blood tests find cancer cells so early that do not appear on standard scans or tests.
“To paint a great future,” he said, “if we knew that tests predict cancer, we could say, ‘Here’s your vaccine.'”
The New York Times. Special
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