JENNIFER BOULDEN

Researchers Thomas Kieber-Emmons and Fariba Jousheghany study the breast cancer vaccine they are developing at the Winthrop P. Rockefeller Cancer Institute at UAMS. The scientists hope to conduct the first safety trials of the treatment this summer.

Though it will be years before it would affect most patients, researchers and clinicians at the University of Arkansas for Medical Sciences have made significant breakthroughs in their quest to design a breast cancer vaccine. By late spring or early summer, the team at the Winthrop P. Rockefeller Cancer Institute is hoping to have the first Phase I clinical trial of the vaccine underway.

The first two phases of clinical trials will take place exclusively at UAMS for a small number of patients. By U.S. Food and Drug Administration requirement, the first trial will focus on safety of the new vaccine, and the second trial will focus on efficacy. Only if the first trials' results are promising, will the clinical trials be expanded to a larger patient population, said Laura Hutchins, MD, director of the Division of Hematology and Oncology and Virginia Clinton Kelly Endowed Chair for Clinical Breast Cancer Research.

"We've already got people contacting us from all over the country that want to come get the vaccine because they are hopeful that it will help their desperate situation," Hutchins said, acknowledging the difficult necessity of turning these patients away. "I don't want to give anyone false hope that we have a treatment that will fix their situation, because that's not where we are yet. It's a long process."

If approved by the FDA for trial, the vaccine will be a first-in-man trial, though it has already shown great success in animal trials conducted at the university, said Thomas Kieber-Emmons, Ph.D., the Josetta Wilkins Chair of Breast Cancer Research at UAMS, who is lead investigator on this project.

"It's very exciting, especially since this is the first of this level of research to be done at the University of Arkansas," Kieber-Emmons said. "It's been difficult. It's been very challenging. But it's also been a lot of fun."

The research, funded by a $2.9 million federal grant, is particularly hard to explain to people, even other researchers, he said. That is because it has roots in many discrete scientific and medical disciplines, all of which his team has drawn upon to design and construct a molecular structure that will induce sustained immunity in tumor cells.

As a graduate student in biophysics, Kieber-Emmons became interested in how molecules interact, particularly how antibodies interact with pathogens. In a post-doctoral fellowship at New York's Roswell Park Cancer Institute, he turned his eye to how antibodies see cancer cells. Simultaneously, he was learning about the mechanisms of structural biology as they relate to molecular recognition, including studying molecular model building and nuclear magnetic resonance imaging.

All of that specialized expertise, plus his years of experience working for a drug manufacturer on the forerunners of cancer drug Rituxan, influenced Kieber-Emmons' work on a breast cancer vaccine many years later at the University of Arkansas.

Kieber-Emmons explained that although the HPV vaccine for preventing cervical cancer is currently the only one approved by the FDA, physicians have been attempting to create cancer vaccines for more than a century.

"Everyone hopes for a cancer vaccine. Operationally, we've had cancer vaccines being tried since the 1800s. People have been using all types of bacterial injections over the centuries," he said, adding that other than HPV, sporadic responses are the best researchers have found over the years.

He said that because the HPV vaccine essentially is a vaccine for a sexually transmitted disease that happens to help prevent a type of cancer, its developers did not run into the same biochemical problems that the many researchers trying to design a vaccine specifically to attack cancer cells encounter. Another distinction is that tumor vaccines are by nature therapeutic vaccines, rather than prophylactic; they are not designed to keep people from getting cancer in the first place.

Kieber-Emmons said much of the research being done by scientists in other places focuses on carbohydrate-based vaccines, since carbohydrates are both constant and highly expressed on tumor cells. The problem, Kieber-Emmons said, is that carbohydrates are notoriously difficult molecules to work with.

"They are hard to synthesize, they are hard to purify, and on top of all that, they are not processed the same way by T-cells as protein antigens," he said. "Consequently, they are a very poor vaccine, at least for tumors—though for infectious disease, they've been very effective."

The UAMS team, led by Kieber-Emmons, has found a work-around.

Kieber-Emmons' breast cancer vaccine combines the concept of biochemical mimicry and drug design principles to create a computer-engineered peptide that looks and behaves like a carbohydrate, without all the molecular drama.

This makes the vaccine much more stable and, in the animals tested, induces a more robust immunological response to what the immune system perceives as a foreign body than do other vaccine iterations.

"We've figured out how to trick the immune system," he said. "We actually convert the structure of a carbohydrate into a peptide. Peptides like to be processed. So for example, if we know how a carbohydrate binds to an antibody, why can't we capture that image and convert that image in the context of a peptide, and redesign the peptide so that it will induce an antibody, plus get the type of cellular responses we're looking for that a carbohydrate can't? That's what we're doing now."

Hutchins explained, "The peptide mimics other carbohydrates that are attached to the body's cells and tricks the immune system into attacking those carbohydrates. Some of those carbohydrates are on cancer cells, so that's how we think the vaccine will work—to direct the immune system to attack the cancer cells."

So far, the team has created a series of these engineered peptides.

"Now we're going to move one or perhaps two of (the peptides) into the clinic," Kieber-Emmons explained. "In our animal models, they do a great job of doing all the things you want them to do. They inhibit tumor cell growth in these animals. You can prolong survival in these animals. They do a lot of neat stuff. But we don't know if they will do the same things in humans until we start these trials."

Hutchins, who said her main role in the project is about to begin as the clinical trials get underway, also said that while it's a tremendously exciting time and they have much hope for the vaccine, it's far from certain that it will work.

"There have been some melanoma trials in which the patients who got a vaccine actually did worse, as far as their melanoma was concerned, than patients who were in the control group," she said. "It is not a given that this is going to work, and it is not a given that we won't see any detrimental effect. That's why we do the trials."

The first group of patients she will test are breast cancer patients who are in remission and have stable immune systems but are at high risk for recurrence of the disease. This trial will be looking at toxicity issues, safety and side effects.

Kieber-Emmons said that the only side effects they are expecting to see are things like possible redness at the site of injection or a fever after the injection.

In Phase 2, the trial will be expanded among more UAMS breast cancer patients to test for efficacy.

Kieber-Emmons said that a later stage of trials will test the immune response against the vaccine, a series of four injections and a booster shot, created in metastatic patients. He said vaccinating metastatic patients is particularly difficult because their T-cells have suppressed their immune system's responsiveness. "We have to be able to turn that immune response back on and then vaccinate, or our peptide will never work. We're working on that now."

Although the vaccine is designed with breast cancer in mind, if it works the way the researchers are hoping, it could help countless more cancer patients.

That's because unlike the HER2-receptor-based vaccines most other breast cancer vaccine research involves, the UAMS vaccine uses molecular ingredients that are expressed on many kinds of tumors.

"There's a lot of HER2 research being done. What sometimes people don't realize is that the expression level of HER2 is really somewhat restricted. There are not a lot of people with HER2 expressed on their tumors," Kieber-Emmons said. "Ours, if it is proven effective, would work for a wider population than the HER2-based vaccines. In fact, not only would it work for breast cancer, but for other cancer indications as well, because the same carbohydrates are expressed on multiple tumor types."

He said the research and the countless regulatory hurdles to jump through for FDA approval of the clinical trials have had the happy byproduct of making UAMS a stronger research facility.

"This level of basic research that translates to the clinical is something brand-new for UAMS," Kieber-Emmons, who helms a team of about two dozen people who work on the project, said. "All the previous clinical trials at UAMS have been under different types of FDA approvals, mostly treatment protocols, that do not require the same level of animal testing that ours requires, and all the ensuing paperwork."

That paperwork included writing more than 150 Standard Operating Procedures, each of which had to be reviewed and approved multiple times by multiple people.

Kieber-Emmons said, "It's really a massive operation that makes the science look almost easy relative to the amount of paperwork that has to be done to document every step. UAMS really rose to the occasion. I could not have asked for a better support staff, both from the Cancer Institute and from the University. Any success we have is just as much theirs. It really takes a team to accomplish something of such scale."

Best case scenario, if the trials were wildly successful and everything was fast-tracked through the FDA drug approval process, Kieber-Emmons estimated that it would still be at least seven or eight years before the vaccine could be manufactured and become commercially available.

Hutchins said she is proud of the work that has been done and cautiously optimistic about the results of the trials, which will take about 18 months to complete. "I think it's a big step for the University of Arkansas that we have a potential treatment that's been developed here from the ground up," she said. "That's always really exciting, and we need more of that. We're hoping that this will be the first of many studies like this."