IT’S BEEN 10 YEARS since Tom Liebert received an experimental cancer vaccine to treat his multiple myeloma, and he still wonders: Did it work?
The question nags at him, but not always. After all, he’s still alive and singing with a barbershop quartet in Fairfield Glade, Tennessee. And while he knows multiple myeloma is currently incurable, it is treatable. “The definition of a cure for me is that I die from something other than myeloma,” says the retired electrical engineer and computer scientist, now 60.
In the fall of 2005, Liebert lived and worked in Boston and was teaching computer science to adult continuing education students at Northeastern University. He was 48 years old and seemed fit, but a combination of symptoms—sudden energy loss and bone pain—spurred him to get a physical that revealed proteins in his urine. A few months later, after moving to Maine, he suffered a compression fracture in one of his vertebrae and was diagnosed with osteoporosis. He began to think the proteins in his urine and the bone disease were related, and in September 2006, blood and urine tests, combined with a bone marrow biopsy of his hip, confirmed that he had stage III multiple myeloma.
Multiple myeloma is a cancer that usually starts in the plasma cells in bone marrow. Common symptoms include bone pain and weakness and fractured bones. The median age at diagnosis is 69; average survival after diagnosis with stage III multiple myeloma is about 29 months.
Liebert’s local oncologist prescribed Cytoxan (cyclophosphamide), an effective chemotherapy for multiple myeloma. He was also in contact with oncologist Paul Richardson at Dana-Farber Cancer Institute in Boston, who told him about a phase II clinical trial of an experimental vaccine.
Liebert had a longstanding interest in microbiology. In graduate school, he worked in a molecular biology research lab and took biology and genetics classes. “The idea of harnessing my own immune system to identify, attack and destroy my own cancer cells had an intuitive appeal to me,” he says.
Researchers have been chasing the idea of treating cancer with vaccines for decades, but the history of the science shows more failures than successes. In recent years, however, treatment vaccines have attracted more interest thanks to advances in immunotherapy, an approach that harnesses the body’s immune system to attack cancer. Clinical trials suggest that personal vaccines, tailored to treat a particular tumor, could help extend survival in patients with hard-to-treat disease.
“We’re excited, and we are hopeful, but [vaccines] are going to require very carefully designed, well-thought-out studies that focus not only on efficacy but on safety,” says neuro-oncologist Mark Gilbert at the National Cancer Institute (NCI) in Bethesda, Maryland.
Preventing Cancer and Treating It
To most people, vaccines mean disease prevention and conjure up memories of receiving childhood shots to prevent measles, mumps, rubella and other infections. Those immunizations use weakened bits of disease-causing microbes to train the body’s immune system to defend itself. They are preventive and proactive; they take care of a problem before it becomes a problem.
The U.S. Food and Drug Administration (FDA) has approved two types of vaccines that prevent cancer by fighting off infections from cancer-causing viruses. One vaccine inoculates a person against hepatitis B, which can lead to liver cancer. The other inoculates people against strains of the human papillomavirus (HPV), which causes the majority of cervical cancers and has been implicated in a number of cancers at other sites, including the mouth and throat, rectum and vulva.
Therapeutic vaccines like the one Liebert was given are different. They treat people already diagnosed with cancer and represent a newer, more experimental area of research. Cancer treatment vaccines are a type of immunotherapy. Clinical trials have shown that some immunotherapy treatments increase survival for certain patients, and these findings have led to FDA approvals of new therapies for metastatic melanoma, lung cancer and other cancers. However, not all patients respond favorably to immunotherapy, and those who do may develop resistance. Cancer treatment vaccines may play a role in extending the benefits of immunotherapy to more patients and for longer periods of time.
Liebert received chemotherapy in Maine and traveled to Beth Israel Deaconess Medical Center in Boston for the vaccine trial, which was led by hematologist-oncologists David Avigan and Jacalyn Rosenblatt. The researchers have pioneered a similar experimental vaccine for people with acute myeloid leukemia (AML).
One opportunity to incorporate a vaccine into a treatment regimen might be after a disease has been reduced through chemotherapy or other treatments, Rosenblatt says. “We want to eradicate residual disease and prevent the disease from recurring,” she says.
The HPV vaccine could reduce rates of certain cancers.
In 2012, cervical cancer killed roughly 266,000 women worldwide, mostly in less-developed countries. According to the U.S. Centers for Disease Control and Prevention (CDC), more than nine in 10 cases are caused by strains of the human papillomavirus (HPV), the most prevalent sexually transmitted virus in the world. HPV infection also causes genital warts and has been linked to many other cancers, including those of the throat, anus, vulva and rectum.
In 2006, the U.S. Food and Drug Administration (FDA) approved the first vaccine that can prevent infection by two cancer-causing strains of HPV. The vaccine, Gardasil, is most effective in people who have not been exposed to HPV. Merck, the manufacturer, sought fast-track approval from the FDA. As a result, the vaccine was approved only for adolescent girls, the population believed to benefit the most from it.
Approving a vaccine only for adolescent girls caused a firestorm and political backlash. Critics questioned the safety of the vaccine, but follow-up data suggest that people are much more likely to die of cervical cancer than to have an adverse response to the vaccine. No deaths have been attributed to the vaccine.
Since then, other vaccines have entered the market, some of which can prevent infection by other disease-causing HPV strains. The CDC now recommends that adolescent boys and girls receive the vaccine before they become sexually active. Data released in 2013 show that infection with cancer-causing HPV strains has decreased by more than 50 percent among girls 14 to 19 in the United States.
However, in the United States only about 63 percent of teenage girls have started the series—a lower vaccination rate than in many developing countries. In Rwanda, for example, about 95 percent of teenage girls have received the vaccine through a government-led effort.
Prescription: Vaccine
In 2010, the FDA approved the first therapeutic cancer vaccine, Provenge (sipuleucel-T), for men whose metastatic prostate cancer has stopped responding to hormone therapy. Clinical trials are investigating dozens more. Recent and ongoing trials are testing vaccines for melanoma and breast, lung, prostate and other cancers.
Most cancer treatment vaccines are customized for a patient and built from a patient’s own immune or tumor cells. That means they can’t be mass-produced and are expensive and arduous to make. (Clinical trials, like Liebert’s, typically cover the cost of a patient’s treatment.) Provenge, for example, costs $93,000 and extends a person’s life by roughly four months on average, according to a 2011 paper in Pharmacy and Therapeutics.
Still, clinical trials of vaccines appeal to people who have exhausted all other treatments, says neuro-oncologist Jason Fangusaro at the Ann and Robert H. Lurie Children’s Hospital of Chicago. Fangusaro runs a phase I clinical trial of a patient-derived vaccine for children diagnosed with certain types of brain and spinal cord tumors. “Many families are willing to try something new because their child is in a situation where there’s no curative option,” he says. “We can’t promise anything because this is uncharted territory, but the potential for benefit is something they’re willing to try.”
For Liebert, being treated was a long and complicated process. Before he received the vaccine, Liebert underwent a stem cell transplant (SCT), often considered the standard of care for multiple myeloma. During an SCT, physicians first harvest stem cells from a patient’s blood or bone marrow. These cells produce lymphocytes, like T cells and B cells, that fight infection in the body. They are soldiers in the immune system’s army. Liebert’s harvested stem cells were stored while he underwent treatment with Alkeran (melphalan), a chemotherapy that suppresses the bone marrow’s ability to make blood cells. After chemotherapy, Liebert’s harvested stem cells were returned to his body to boost his recovery and make new blood cells.
How to Make a Vaccine
“Cancer is really, really smart when it comes to figuring out how to evade the immune system,” says Gilbert at the NCI. T cells, B cells and other cancer fighters lurk in the blood around cancerous growths, but they don’t attack. That’s partly because tumor cells release proteins into the blood that effectively blind the immune system.
The challenge lies in finding a way to unmask a tumor. Gilbert is leading a nationwide clinical trial of a vaccine for patients with glioblastoma, an aggressive form of brain cancer. Researchers on the trial are using a vaccine synthesized from each patient’s tumor. It works, in a way, by revealing the cancer’s fingerprints to the immune system.
For the multiple myeloma and AML vaccines, Rosenblatt and Avigan combine a patient’s cancer cells with harvested dendritic cells. These are the generals of the immune system; they tell T cells which invaders to attack. Fusing them with tumor cells “trains” the dendritic cells to recognize tumors; when they are returned to the body, the dendritic cells can mobilize T cells to attack. Early results of this approach are promising: In December 2016, Rosenblatt’s group reported that 12 of 17 patients treated with a dendritic cell vaccine for AML remained free of disease recurrence after five years.
Rosenblatt’s group also fused dendritic cells with tumor tissue to develop the multiple myeloma vaccine that Liebert received in 2007. Before he began the stem cell transplant, Liebert underwent a bone marrow aspiration, which meant removing tissue from his iliac crest—the ridge of bone at the top of the hip. The vaccine recipe called for about two tablespoons of tumor tissue. Liebert was conscious for the procedure. “It felt like getting kicked by a mule in your back,” he recalls. Producing the vaccine took about three weeks.
As a phase II study, the trial was designed to show that the vaccine, administered after a stem cell transplant, was safe and effective, which it was. Liebert never learned about his specific results, but Rosenblatt and her team reported in 2013 in the journal Clinical Cancer Research that 31 percent of patients had a complete response—which means no detectable signs of cancer—after the stem cell transplant. That number jumped to nearly 50 percent after receiving the vaccination.
“I wish they had been able to tell me if I had a clinically significant response,” he says, but the results weren’t provided to participants in the trial. (Some clinical trials do provide results to participants.) Whether or not he was in the group that responded to the vaccine, he did have a long stretch without symptoms. “For two solid years after the trial, I was clean as a whistle.”
The results of that trial set the stage for a bigger one: Over the past year, researchers from 15 cancer centers in the United States traveled to Beth Israel Deaconess to learn how to synthesize dendritic cell vaccines. They are now collaborating on a national phase II trial of the vaccine for multiple myeloma patients. Rosenblatt hopes the study will help an even larger swath of the patient population.
Combining Vaccines With Other Treatments
The real clinical value for vaccines is likely to be as part of a combination therapy that includes other types of treatment.
In the glioblastoma trial that Gilbert oversees at the NCI, for example, patients receive both a vaccine made from proteins taken from their own cancer cells and a checkpoint inhibitor, a type of immunotherapy that effectively releases the brakes on the immune system. The vaccine reveals the tumor; the checkpoint inhibitor activates T cells to attack. Gilbert and other researchers hope this strategy can overcome the tumor’s strategies for suppressing the immune system.
“Imagine this huge army going in there, and if you find some resistance, you just overwhelm it,” Gilbert says.
In the case of the multiple myeloma vaccine, researchers suspect the experimental dendritic cell vaccine extends the benefits of stem cell transplants, which have already been shown to delay relapse by over a year. Rosenblatt thinks that for blood cancers, as for solid tumors, future treatment regimens will likely include combinations of immunotherapies. “But first we have to understand which combinations have the best synergy,” she says.
Over the years since being treated with the vaccine, Liebert has had relapses and received a number of therapies. In 2013, he was treated with radiation for a concentration of myeloma cells in a neck vertebra; in 2015, blood tests and a bone marrow biopsy showed that he had relapsed, and he received Kyprolis (carfilzomib) and Pomalyst (pomalidomide).
“You know you’re going to relapse pretty much until you reach an endpoint, which is either A, your death, or B, they find a cure,” he says. “I never thought I’d hit 60.”
Given the choice, he says he’d participate in the vaccine trial again—even without knowing the results. Rosenblatt notes that some people may be skeptical of clinical trials and afraid to try something that’s not proven. “Other people, at the other end, may have unrealistic hopes about what a trial can offer,” she says. It’s up to the researchers, she adds, to present information in a clear way that conveys the possible outcomes.
It’s also up to the researchers to identify the patient population most likely to respond. “If it works, I hope it works in everybody,” says Gilbert. “If it works in some people and not in others, we need to figure out why.”
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