note_-scientists
Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.
Tiffany O’Keefe will tell you that her life is pretty normal — at least as normal as it can be with three teenagers at home. For this Washington elementary-school teacher, normalcy is a huge accomplishment.
In 2004, O’Keefe, then 32, was diagnosed with a cancerous tumor in her lung after she showed up at the ER with shortness of breath. In the course of the next decade, she lost that lung, endured miserable side effects from chemotherapy, and ran through treatment after treatment as her cancer recurred four times.
More than three years ago, O’Keefe enrolled on a clinical trial and became the first person ever to receive a new type of experimental cancer vaccine, which uses a modified virus to teach patients’ immune systems to kill their tumors. Her cancer shrunk to a fraction of its former size and, though it’s still present, has stayed quiet since then, allowing that precious normalcy to return.
“I used to tell the doctors, ‘I just want to see my kids graduate from high school, and that’s good — I just want to get them raised,’” O’Keefe said. Now, her oldest is 18, and she’s looking ahead to new milestones — like grandkids someday. “I used to think that might never happen for me,” she said.
Given that her very rare and aggressive cancer, a type of sarcoma, proved so resistant to everything else doctors had thrown at it, her cancer’s response to this new experimental therapy was “dramatic,” said Dr. Seth Pollack of Fred Hutchinson Cancer Research Center, who treated O’Keefe on the trial.
The overall outcomes from O’Keefe’s trial and a related clinical research study were promising enough, the researchers reported earlier this summer, to continue the vaccine’s clinical development. But among all 31 participants on the Phase 1 trial, the fact that O’Keefe’s cancer shrunk so much and has stayed that way for so long makes her special — and an important proof of principle, Pollack said.
“I think this case shows that this type of vaccine could work,” said Pollack, whose case study on O’Keefe’s data was published today in the Journal of Immunotherapy. “It definitely can make immune responses that are relevant and clinically meaningful and can make a difference for patients.”
An unexpected ordeal
When O’Keefe was first diagnosed with a tumor, she was so young and otherwise healthy that the idea she might be entering into a yearslong ordeal didn’t occur to her. Her local doctors didn’t seem particularly concerned, she said. She’d just get the mass in her lung taken out, and that would be that.
“I was nervous, but I wasn’t in a panic,” O’Keefe said.
But soon, everything changed.
O’Keefe remembers her surgeon walking into the hospital room where she was recovering from the procedure to remove the tumor they’d thought was benign. There was a doctor with the surgeon she’d never seen before — an oncologist, it turned out.
They’d been wrong, they explained. Her tumor had turned out to be a type of aggressive cancer, synovial sarcoma, so rare that the oncologist had never personally seen a case before.
“I was like, ‘wait a minute, no one knows what they’re doing now,’” O’Keefe said recently by phone from Washington’s Olympic Peninsula, where the 45-year-old lives with her family and teaches the second grade. “That’s when it became real.”
Sarcomas are a diverse group of cancers that affect connective tissues, including bone, muscle, cartilage, nerves and fat tissue. According to the online medical resource Medscape, only about 800 Americans, mostly younger adults and adolescents, are diagnosed every year with synovial sarcoma, a subtype that affects certain soft-tissue cells found throughout the body.
Diagnosis with synovial sarcoma threw O’Keefe into a punishing regimen of inpatient chemotherapy that she squeezed in during the weekends her ex-husband had custody of the children, then ages 2, 4 and 6. (The couple’s divorce was finalized the month O’Keefe’s tumor was discovered.) She was also juggling a master’s degree program on the side as she dealt with the “horrible” side effects of her regimen, including painful sores and low blood counts that frequently landed her back in the hospital for blood transfusions.
“It was a really long six months of not knowing what was going to happen, and being scared, and trying to raise my kids and keep them calm and feeling secure,” O’Keefe recalled.
She got through it. She finished her degree and went to work at a local school.
But cancer wasn’t done with her.
The list of treatments O’Keefe went through as her cancer recurred throughout her lung and chest is so long and complex she now has trouble keeping them all straight. First recurrence, in 2007: more surgery. Second recurrence, in 2009: chemo, surgery and radiation. Third recurrence, in 2012: more chemotherapy and the complete removal of her left lung. Fourth recurrence, in 2013: a chemo pill that stabilized her disease but caused her blood-clotting platelets to plummet, forcing her to go off it by the end of that year.
Her cancer started growing again. Surgery was no longer an option, and chemotherapy had proved so toxic for her that she couldn’t bear the thought of doing any more.
Becoming participant No. 1
Her doctors at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner, thought more chemo likely wouldn’t have helped much anyway. At that point they were worried that she would not survive another year, said immunotherapy researcher Pollack.
Pollack was not O’Keefe’s primary oncologist for most of her courses of treatment but had been discussing potential trial options with her and her care team at SCCA. Initially, O’Keefe was skeptical — in great part, she recognizes now, because she was scared of facing the idea that her disease was quickly becoming terminal.
“I was like, ‘No way, I don’t want to be your guinea pig, see you later, nope, sorry, Dr. Pollack, I don’t want to talk to you,’” O’Keefe said. “I always liked him but I just didn’t want to deal with him.”
But when Pollack told O’Keefe about the new vaccine trial, she was curious. The study would involve no more chemo, she learned. Side effects were expected to be much milder than what O’Keefe had already been through. And they’d already tested her tumor tissue in the lab and found that its molecular profile was just right to be targeted by the experimental vaccine.
“Having known they had a response in the lab, I was way more willing to go for it,” O’Keefe said. She remembers thinking, “If it’s good, it’s good. But if it isn’t, at least we can learn something from it that will help other people.”
She got her first injection of the experimental vaccine in May 2014, as participant No. 1 on the trial.
A new strategy plays out
The cancer vaccine that O’Keefe received, dubbed LV305 and produced by the Seattle-based Immune Design, works in a totally different way from the infection-preventing vaccines people are most familiar with, like the flu shot. Not only is it designed to treat disease rather than prevent it, it employs that age-old threat to human well-being — viruses — as a tool for health.
The vaccine contains a specially designed virus that was created for a single purpose: activating a cancer-specific immune response. The virus targets immune cells called dendritic cells that act as mini Paul Reveres, rousing your natural disease-fighting army and pointing it toward an enemy. In this case, the enemy was cancer cells bearing a telltale molecular flag.
After three sets of vaccine injections over six weeks during the summer of 2014, a scan showed that O’Keefe’s cancer had stopped growing. At her next scan, two months later, her cancer had shrunk a bit. A couple months later, her cancer was only three-quarters its original size. By 2016, two years after her first injection, only 15 percent of her original tumor mass remained. It has stayed there ever since, without additional treatment.
Extensive studies of O’Keefe’s blood and tumor-tissue samples in Pollack’s lab have shown that her immune system greatly stepped up its response to her cancer after vaccination and has remained on alert ever since. They’ve also found some clues as to why O’Keefe’s response might have been more dramatic than that of any other patient’s on the trial. For example, before she was even vaccinated, her immune system’s killer cells already recognized the telltale cancer flag programmed into the vaccine.
“When everything fits together with clinical response and immune monitoring, all in the same patients where their disease regresses, that shows you for sure that the vaccine has the potential to do these effects,” said Pollack, who is now involved in trials testing new formulations of the vaccine in new treatment combinations. “And then you can go out and try to figure out how to make the vaccine work best.”
Today, no particular side effects from the experimental therapy stick in O’Keefe’s mind — a night-and-day contrast from her experience on chemo.
She is a bit short of breath — she has only one lung, after all — but, otherwise, the fact that she has cancer doesn’t circumscribe her life today. “I can do most anything,” she said.
O’Keefe knows she has had one of the best responses to the vaccine of any of the patients on the trial and feels “very fortunate,” she said. For now, she prefers her doctors not to tell her where her remaining cancer is at her checkups. She knows herself well enough: Every little ache or pain near the tumor site, wherever it is, would plunge her into a morass of anxiety about whether her cancer was growing again. And, for now, she knows there’s nothing more she could do to keep it from coming back if it wanted to.
“I just don’t want it to be what my life is about,” she said.
A look at a recent family photo, O’Keefe’s arms around her kids, makes it clear: It’s not.
Immune Design, whose scientific co-founders include Fred Hutch’s Dr. Larry Corey, sponsored the trial. MD Anderson’s Dr. Neeta Somaiah led the trial, but Pollack played a large role in designing it, carrying out lab studies and treating patients. Via Fred Hutch, the company funds some studies in Pollack’s lab on this and other products, but Pollack has no personal financial interest in the company.
What do you think about Tiffany's story? Tell us on Facebook.
