Haidong Dong, M.D., Ph.D. reflects his cultural heritage when he explains that it will be his students who will find cures based on the foundation of knowledge he is now building.

"I got into research because I grew tired of not being able to offer my cancer patients in China any alternatives," he says. "You'd do exploratory surgery, see the extent of the cancer, and close them back up." He conducted research in his homeland as well as Japan before coming to Mayo Clinic to explore immunotherapy as an alternative or adjunct to current cancer treatments. He says he knows that may be a long-term, even multi-generation effort.

Discovering B7-H1

One success he vividly recalls is the discovery of the first B7 homolog molecule (B7-H1), which became the cornerstone for an entire line of research (Nat Med. 1999 Dec; 5(12):1365-9).

"I remember we were doing final work on the sequencing in December of '98, and we published in December of '99," he says. "It was a co-stimulatory molecule that had lost its anti-tumor abilities and was instead protecting the tumor and allowing it to grow."

Then came the discovery of B7-H2 and B7-H3. (There was no real B7-3; it turned out to be something else and the naming succession just continued from there). Soon Mayo researchers discovered a series of homologs in the B7 family, such as B7-H1, B7-H2, B7-H3, and B7-H4.

B7-H4, when active, helps renal cell carcinoma grow and spread by blocking the body's immune system. Renal cell carcinoma makes up 85 percent of the kidney cancers in the United States and tumors with B7-H4 on the blood vessels are the most aggressive type. The goal of Mayo Clinic immunologists is to create an antibody that targets this molecule, so as to attack these tumors. In the meantime, B7-H4 serves as a biomarker, telling physicians that they must treat such cases with the most aggressive therapies available (Proc Natl Acad Sci U S A. 2006, 103:10391-6).

Both B7-H4 and B7-H1 are present in the body and in normal times serve as a modulator of the function of the immune system. That is, they act as a stop switch on the natural immune function so the system doesn't go too far and attack the body itself. It's when these regulatory cells are co-opted by cancer tumors that they become a roadblock to immunotherapy. The goal is to disarm these guards, via a molecular blocking mechanism, leaving the tumor defenseless.

The potential impact of the Mayo B7 research is wide. Dr. Dong ran down the potential target cancers, "Breast, kidney, lung, prostate, stomach, liver..."

Mayo investigators discovered B7-H3 in 2001. Recently, a Mayo team led by Eugene Kwon, M.D., identified it as the first biomarker to predict the outcome of prostate cancer (Cancer Res. 2007, 67:7893-900). From examining levels in prostate tumors removed from 338 patients, Dr. Kwon was able to establish that those with high amounts of B7-H3 were four times more likely to experience cancer progression - that is to have aggressive prostate cancer, in contrast to the typically slow moving cancer that is watched rather than treated, simply because its progression is so slow. Moderate levels of B7-H3 also indicated a 35% increased risk of cancer recurrence.

Dr. Kwon says knowledge of the B7 family will be a boon in advancing "tailored" cancer treatments. "This is the way of the future. Using molecular signatures will facilitate for the first time a truly individualized approach to prescribing the most appropriate therapy for each patient."

The Pickup Truck Analogy

Dr. Dong, meanwhile, has been trying to "soup up" the engine of his "pickup truck." He considers the pickup an apt analogy to explain immune system function in this case. The engine represents the body's T cells, the killer cells that normally would "see and destroy" tumors.

"Everyone has T cells, but they just don't swing into action automatically," he explains. "T cells need to be activated by two factors, one an antigen and the other, a co-stimulatory molecule, such as the B7 group. "

The load in the bed of the pickup truck is tumor that must be dealt with. The larger and more resistant the tumor, the greater the work placed on the engine. What Dr. Dong is looking for is the best way to fuel or spark the T cells to action.

"Not only do we need to know how to jump-start this engine, we also need to know what is the best time to rev it up," says Dr. Dong. "Indications are that between the second and third week of a four-week tumor progression in mice is about right."

The researchers need to find out if that correlates to the same tumors in humans - they think it does, but need to calibrate it. The idea is to apply this "boost" in combination with chemotherapy. First says Dr. Dong, they will lighten the load in the truck bed by shrinking the tumor through chemo. "Then, at the right time, we send in our engineered antibodies to neutralize the negative effect of B7-H molecules."

Dr. Dong's team describes this in the Journal of Immunology (J Immunol. 2007, 179: 2860-69) and how they use a vaccine method to deliver the tumor antigen to the immune system (antibody to B7-H1) to disrupt the tumor's shields and allow the newly stimulated T cells to do their work. As he explains his analogy, it's hard not to envision a pickup bristling with commandos bursting through the wall of a fortress.

A New Antibody

Still another B7 molecule is under study... this time called B7-DC. The principal investigator is Larry Pease, Ph.D., head of Mayo's immunology department and long-time collaborator of both Drs. Dong and Kwon.

B7-DC (for dendritic cell, a branching cell that affixes to tumor surfaces) has the immune potential to combat cancer -- or at least that's the indication from all the preliminary studies on both animal models and human cells in the laboratory. Over the last several years Dr. Pease's team has isolated an antibody that they think can activate the anti-tumor immunity of B7-DC. That antibody was identified in the plasma of a patient with Waldenstrom's macroglobineumia, a disease that inhibits optimal function of proteins in the blood.

An otherwise healthy Mayo patient with the disease donated enough plasma to allow researchers to develop a serum containing the antibody for research use. That serum is ready for testing in a phase one, "proof of principle" clinical trial in which the team will determine the serum's safety and its effectiveness against metastic melanoma. Melanoma is a deadly cancer that usually starts on the skin, but can spread quickly anywhere in the body. "Metastic" simply means to change form and spread.

Dr. Pease is working with Mayo's Svetomir Markovic, M.D, Ph.D., a national leader in melanoma research. The hope is that the antibody will cross link B7-DC molecule on the surface of dendritic cells, stimulating them to mount an invigorated immune reaction. Much of this would not have been possible without the team science that so closely integrates efforts of physician investigators with basic scientists, nor without Mayo's unique patient population base from which researchers observe conditions that lead to new questions and ideas. Those same patients participate in research by donating analytical samples or by taking part in clinical trials. And then there is Mayo's ability to attract the funding to conduct the research. Dr. Pease's work mentioned here depends on multiple federal grants, individual philanthropy, support from the Mayo Clinic Cancer Center and Mayo's Discovery Translation Research Fund. The basic discovery of a new type of antibody to it's translation into a possible cancer immuno-therapy again exemplifies Mayo Clinic's comprehensive approach to attacking disease and finding cures for its patients and patients everywhere.

- Bob Nellis