Wednesday, January 28, 2009
A polymer device trains immune cells to shrink tumors.
| Polymer power: A polymer implant acts as an immune-cell training center. Immune cells lodge in its many holes and are exposed to chemical signals that encourage them to attack tumors. This image was made with a scanning electron microscope.
Credit: Omar Ali
One of cancer's cleverest tricks is its ability to hide from the immune system. A new approach to cancer treatment called immunotherapy could spare patients at least some of the grueling battery of chemotherapy treatments by retraining the body's own defenders--the cells of the immune system--to recognize and destroy tumors. Now researchers at Harvard University have developed a simple way to do this inside the body: a polymer implant attracts and trains immune-system cells to go after cancer.
The experimental approach has shown great success in animal studies, increasing the survival rate of mice with a deadly melanoma from 0 to 90 percent. The implant could also be used to treat diseases of the immune system such as arthritis and diabetes, and, potentially, to train other kinds of cells, including stem cells used to repair damage to the body.
The usual methods for cancer immunotherapy are complex and have had little success in clinical trials, says David Mooney, a professor of bioengineering at Harvard who leads the development of the implant. First, immune cells called dendritic cells are removed from a patient's body; then they're exposed to chemical activators and cancer-specific antigens. These cells are then injected back into the patient, where they should, in theory, travel to the lymph nodes and activate another group of cells called T cells, training them to attack a tumor. But dendritic cells are fragile, and while this approach has increased survival in mice, it hasn't caused tumors to shrink in clinical trials with humans.
"When you transplant the cells, virtually all of them die, and you have very little control over what they do when they're reimplanted," says Mooney. So his team took a different approach to the problem, realizing that "perhaps we could do all this inside the body."
Mooney and his research group constructed a polymer that can do inside the body what complex immunotherapies do outside it. They describe the design and performance of an implant for melanoma in the current issue of Nature Materials. The polymer has a history of safe use in humans (in biodegradable sutures, for example). First, it attracts dendritic cells by releasing a kind of chemical signal called a cytokine. Once the cells are there, they take up temporary residence inside spongelike holes within the polymer, allowing time for the cells to become highly active.
The polymer carries two signals that serve to activate dendritic cells. In addition to displaying cancer-specific antigens to train the dendritic cells, it is also covered with fragments of DNA, the sequence of which is typical of bacteria. When cells grab on to these fragments, they become highly activated. "This makes the cells think they're in the midst of infection," Mooney explains. "Frequently, the things you can do to cells are transient--especially in cancer, where tumors prevent the immune system from generating a strong response." This extra irritant was necessary to generate a strong response, the Harvard researchers found.
When implanted just under the skin of mice carrying a deadly form of melanoma, the polymer increased their survival rate to about 90 percent. By contrast, conventional immunotherapies that require treating the cells outside the body are 60 percent effective, says Mooney.
Robert Langer, a pioneer in developing drug-delivering polymers and an Institute Professor at MIT, says that Mooney's work is "a really beautiful combination of materials science and cell technology."
Accomplishing the entire immunotherapeutic process inside the body using a common polymer is "incredible," adds Peter Polverini, dean of dentistry and a professor of pathology at the University of Michigan, and a specialist in oral cancer. "From the standpoint of efficacy and efficiency, this is a huge advance." For patients, he says, a subcutaneous implant would be "far less burdensome" than doctors removing and reimplanting cells.
Mooney developed the polymer systems with more than melanoma in mind, however. He hopes to develop similar implants for treating other types of cancer, which should simply be a matter of changing the antigen carried by the polymer. But the approach could also be used to treat other kinds of immune disorders. For example, different chemical signals could dampen immune cells' activity in order to prevent transplant rejections and treat autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, which result when the immune system attacks normal tissues. Mooney also hopes that the polymer system can train a different class of cells altogether. Just as fragile dendritic cells seem to respond better to being trained inside the body, this might be a more effective way to recruit and reprogram stem cells.
If proved in people, the cell-training polymers might also bypass some of the regulatory hurdles and expense faced by cell therapies, since devices are more readily approved by the Food and Drug Administration. Indeed, Mooney predicts that the therapy will move quickly through safety tests in large animals (the next step before human trials), and he expects to bring the cancer immunotherapy to clinical trials soon. "All the components are widely used and tested, and shown to be safe," he says.
One thing that remains to be proved, however, is whether the treatment is effective over the long term--whether the body will recognize the cancer cells months and even years later, after the polymer has biodegraded. Most cancer deaths are caused by secondary tumors called metastases that can arise from just a single cell that leaves the primary tumor. The immune system's ability to remember disease-causing agents over the long term is one of the reasons that immunotherapy for cancer seems so promising. Once the cells have been trained to recognize and attack a tumor, the immune system should be prepared to combat cancer recurrence. Mooney says that he's currently working on long-term studies. "Just think what the benefit would be to patients to have their immune system reprogrammed at will to fight disease in a sustained fashion," says Polverini.