Back to Table of Contents | January 2012

Face to Face

Tumor Fighter

John Ohlfest, Ph.D., is on a quest to find less toxic, more effective treatments for brain cancers.

By Kim Kiser

John Ohlfest’s eyes light up when he picks up a piece of paper showing six images of a brain. The MR images—three sets of two views—show four tumors including a large one above a ventricle slowly disappearing over five months. They belong to one of the nine patients who are participating in a Phase 1 clinical trial of a vaccine Ohlfest and his staff have developed to fight gliomas—aggressive brain tumors that are known for their ability to outsmart conventional treatment. For Ohlfest, an associate professor of pediatrics and neurosurgery at the University of Minnesota and a McKnight Land-Grant professor, this accomplishment trumps all other honors he has received in his short-but-prolific career. “I’ve had papers published, received grants, and had press coverage. But never anything like this,” he says of the patient’s response.

For Ohlfest, who directs the Ohlfest Brain Tumor Lab, this is what being a cancer researcher is all about: coming up with treatments that can save lives and help patients avoid the devastating side effects of radiation and chemotherapy. “Our goal is to make sure that no cancer patient has to undergo chemotherapy,” he says during an interview in his office—an orderly cubicle that guards the entry to the lab where researchers quietly attend to their work. “Patients like the sound of that. Oncologists tell me I’m crazy.”

But Ohlfest is proving that the idea isn’t so crazy. Since his lab opened in 2005, he and a team of 15 or so researchers have been collaborating with staff from the veterinary school to engineer a vaccine from brain tumor tissue that can direct the immune system to kill those very tumors. Working with Elizabeth Pluhar, DVM, a veterinary surgeon, Ohlfest began testing the vaccine in dogs with gliomas and meningiomas in 2008. In November 2010, he began testing a similar vaccine in humans whose gliomas had recurred despite surgery, radiation, and chemotherapy. “This is their last chance,” he explains.

Some of the dogs that have undergone treatment have shown no recurrence of the tumor; some are still alive two years after treatment. As for the human patients, Ohlfest is cautiously optimistic. “We have a functional vaccine that appears to be safe and has some effect preliminarily,” he says.

For patients with brain tumors, this is reason for hope. “We haven’t made a significant impact on the outcome of many brain tumors in four decades,” says Christopher Moertel, M.D., a pediatric neuro-oncologist and director of the pediatric brain tumor program at the University of Minnesota. “But when you compare this with other Phase 1 trials that we’ve run, we’re very pleased that patients’ quality of life has been preserved or enhanced … and that we are getting hints that we may be helping the immune system have an impact on brain tumors.”

Research Renegade
The fact that Ohlfest and his staff began developing and testing a vaccine in humans just two years after they first tested one on dogs reflects his philosophy about research—one that challenges the status quo. “I’ve been very frustrated by a culture that seems to do what I call research for research’s sake. There are a lot of brilliant minds that get so focused on answering a question that they lose sight of the fact that the reason the taxpayers are paying the NCI [National Cancer Institute] to fund our jobs is to cure cancer, period,” he says.

One of the biggest problems in his opinion is that research often starts and ends with mice. “We keep testing things in mice, and they always work. Then we take them into humans and they almost never work. If that were a business model, the business would go bankrupt, yet this is the model we have,” he says. When he got his lab up and running, he vowed that his work wouldn’t end with animals. “I love dogs; I have one, but it can’t end there,” he says.

Ohlfest’s determination to find a cure stems from having watched his grandmother suffer. During his sophomore year at Iowa State University in Ames, she developed ovarian cancer that quickly spread to her lung, kidney, and liver. She was told she had only three months to live. After multiple surgeries and chemotherapy, she appeared to have beaten the disease. But her cancer returned, and she died while Ohlfest was still an undergraduate student.

What made an impression on Ohlfest wasn’t so much the effects of the disease as it was those of the treatments. “I specifically remember one time when she took interferon. She was very ill, and she was just sitting there shaking. It gives you the worst fever you’ve ever had for days,” he says. “I remember thinking, ‘This is crazy.’” Ohlfest, who didn’t have a direction when he started college, suddenly found his calling: to develop cancer therapies that didn’t have devastating side effects. From that point on, he aced his undergraduate classes. He went straight to the Ph.D. program at the University of Minnesota, finishing in a record three years and earning his doctorate in molecular cellular developmental biology and genetics in 2004. When another institution tried to hire him, the University of Minnesota countered and let him start his own research program in 2005—a coup for the researcher who was only 28 years old at the time.

“Everyone across the country and around the world knows that this guy is really smart. He knows the field, he knows where he’s going,” Moertel says. “For someone his age, he’s a star.”

Dynamic Duo
As he was establishing his lab, Ohlfest attended a seminar by a veterinary oncologist who talked about the fact that cancer is the No. 1 cause of death in adult dogs. He learned that an estimated 14,000 dogs get brain cancer each year and that most of them are euthanized. (Ohlfest’s own dog, Tillie, a Staffordshire terrier, recently went through surgery to remove a mast cell tumor from her leg. He plans to create a vaccine for her as a follow-up treatment.) “It was a no-brainer,” he says of his next step. “I wanted to do studies where you took out the tumor and used it to make a vaccine.”

Ohlfest found a partner who was “willing to do something risky that hadn’t been done before” in Pluhar. Together, they began recruiting dogs with brain tumors for a study. Pluhar would remove the tumor. If it proved to be a glioma, the tissue was sent to Ohlfest’s lab, where cells would be cultivated, killed, and turned into a vaccine.

Making the vaccine wasn’t as simple as it sounds. Ohlfest and his team needed to find a medium in which the cells would grow and a substrate to which they would attach. “We went through painstaking failure with growth media,” he says. Then there was the issue of the environment. Most labs grow cells in an incubator that is perfused with air that has a 20 to 21 percent oxygen concentration, the amount in the air we breathe. Tissue in tumor cells has an oxygen concentration of 1 percent or less. “So it’s very unnatural for a tumor cell to grow when exposed to that level of oxygen,” he says of the 20 percent environment. They found that growing tumor cells in a low-oxygen environment results in a vaccine that’s much more likely to provoke an immune response.

When Ohlfest and Pluhar treated the first dog in 2008, a shepherd mix named Batman, they grew cells from his tumor at 5 percent oxygen. But Batman’s case took an unexpected turn. Even in those optimal conditions, the tumor cells didn’t grow quickly enough. So they used cells from another dog’s tumor to produce enough vaccine to finish his treatments. They didn’t know if this approach would work; but the vaccine produced the hoped-for immune response, killing Batman’s remaining glioma cells and preventing a recurrence. (Batman died of other causes in January 2010; he was cancer-free at the time.)

From Dogs to Humans
With that finding, Ohlfest began thinking about extending the concept to humans. He wondered whether glioma cells from one patient could be used to treat another patient who was inoperable. And could another patient’s tumor cells be used if a patient’s own cells didn’t grow fast enough, as was the case with Batman? “These are practical issues that companies trying to make cancer vaccines from tumors are facing,” he explains. His team began an initiative to characterize a panel of primary human glioma samples to try to identify markers that were present on the majority of those tumors, then develop a cell line that had the most common markers. The theory was that those cells could be used to evoke an immune response in patients whose tumors had the same markers. And if they could make cells that were renewable, they could create a product that would be readily available.

After looking through a number of cell lines, they came upon one that had every marker they sought and then some. They named the line GBM6 for the protein component of the vaccine. (Ohlfest says this cell line, along with their efforts to grow cells in a low-oxygen environment, sets their work apart from other efforts to create vaccines for cancers.) Just over a year ago, they began testing a vaccine created from those cells in humans. He and Moertel recently enrolled the ninth and final patient in the first phase of that trial. (The university is looking for an industry partner to produce larger quantities of the vaccine for a Phase 2 trial.)

Unlike the dogs, who received the vaccine as a first-line treatment, all of the human patients in the Phase 1 trial had undergone conventional treatment without success. This inspired Ohlfest and Pluhar to do additional studies to find out whether exposure to other treatments could make the vaccine more or less effective in dogs. So far, they are finding the effects of chemotherapy on a person’s ability to mount an immune response to the vaccine are much worse than they imagined. “It’s very devastating what chemotherapy does,” Ohlfest says. He and his team are also developing and testing new adjuvants for the vaccine that can trick the immune system into thinking the tumor is a virus and generate an immune response. “It’s been effective with things like measles and smallpox,” he says.

In addition, researchers in his lab have sequenced tumor cells to identify all mutations, not just the ones they’re trying to attack with the vaccine. They’re also trying to make a new synthetic version of the vaccine using the genetic information they extract from a patient’s tumor cells. “We call it a personalized genomic vaccine,” he says. They are currently trying to prove the concept in mice, then will begin testing it in humans. “We don’t want to stop or even get side tracked,” he says.

In early 2012, Ohlfest and Moertel plan on opening another clinical trial in which they will use cells from the GBM6 line to create a vaccine for pediatric patients with diffuse intrinsic pontine gliomas, a cancer of the brainstem that is aggressive and difficult to treat. They plan to test it in combination with radiation therapy in children who have never received chemotherapy. “We think the radiation and vaccine are more likely to work together than the chemo and the vaccine, which we know can work against each other,” he says.

Ohlfest hopes those children will respond like the patient in the glioma trial whose tumors appear to have regressed and who is doing well. “I want to see more people walking out of here feeling like he feels,” Ohlfest says of that patient. Again, he picks up the images of that man’s brain and reflects on them. “Seeing that is addicting,” he says. “I want more, I want more.” MM

Kim Kiser is associate editor of Minnesota Medicine.