Fighting Disease in Situ

A scanning electron microscope image reveals the porous nature of a bioengineered disk where immune cells can reside and be programmed for vaccination.

The disks at the center of Dr. David Mooney's current cancer research don't appear very powerful. Grayish-brown circles with the texture of a dry, hardened sponge, they are dwarfed by a fingertip and snap in half easily. But if recent work on melanoma therapies by the McKay professor of bioengineering and his team are any kind of harbinger, these tiny disks could become cancer's biggest challenger.

Cancer is a tough enemy. Against most diseases, the human immune system is a stalwart defender, equipped with a huge arsenal of molecular weapons to fight off bacteria, viruses, and all sorts of other harmful foreign invaders. But cancer flies under the radar: created by the body, it is camouflaged by familiar proteins the system has learned to view as harmless.

The relatively new field of cancer immunotherapy seeks to resolve this quandary by retraining the body's defenses to seek out and destroy cancer cells it would normally pass by. So far, the vaccines and therapies developed using this approach typically involve removing cells from a patient's body, programming them externally, and then reinjecting them. At that point, the hope is that the cells will travel to the lymph nodes and activate tumor-fighting killer T-cells.

"But there are limitations with that protocol," says Omar Ali, a postdoctoral fellow and a principal collaborator with Mooney. "Specifically, when you inject the cells back into the patient, many of them--which you have spent so much time programming--will die." Once trained outside their natural environment, Ali says, the cells have trouble readjusting to the body, leaving only 1 to 2 percent to mobilize cancer-fighting T-cells.

Mooney's team has solved this problem by finding a way to deliver cancer therapy from within. Mooney had been working with biomaterials and implantable systems in his research for years, stimulating blood-vessel growth and bone regeneration using small subcutaneous disks: just the kind of device that might allow researchers to recruit immune cells and activate more efficient attacks on the cancer.

As they detail in a recent issue of Nature Materials, Mooney's team began their research by locating a good internal recruiter--a special protein that attracts dendritic cells, the immune--system workers that instruct T-cells to attack.

Their delivery method was a thin, eight-millimeter polymer disk that they implanted under the skin of mice with an aggressive melanoma. Reacting to the internal recruiter, dendritic cells sought out the disk, where they were activated by two additional items it harbored: antigens to train the cells to seek their specific cancer target, and so-called "danger signals," which mimic infection and energize the cells. Then the dendritic cells migrated to the lymph nodes to create armies of tumor-specific T-cells.

The addition of the "danger signals" proved crucial, sending 13 percent of the cells toward the lymph nodes, an improvement of more than 10 percentage points over results from external treatments. That outcome, coupled with the apparently more lasting benefit of internal manipulation by the activated dendritic cells, produces a qualitative as well as quantitative effect, says Mooney. The mice--which had been dying from the melanoma at around the twenty-fifth day--began surviving at a rate of 90 percent.

In addition to the promising results, there were other practical benefits: the disks cost only about $300 to manufacture; external treatments, Ali says, can take up to a month to prepare and can cost up to $10,000.

Working with Harvard's Office of Technology Development (see "Retooling Tech Transfer," January-February 2008, page 57), the findings have become the foundation of a start-up company, InCyTu (a play on in situ, and a nod to Mooney's bioengineering models). The team expects to begin clinical trials by the end of the year, and hopes for reasonably quick acceptance because the Food and Drug Administration has already approved most of the elements they are working with, including the disk. They see the possibility of treating a host of diseases beyond cancer, including administering stem-cell treatments, with this novel delivery method.

Even if the clinical trials result in something more modest than a cure, says Ali--if the technique enhances survival rates or gives chemotherapy a better chance to work--it could be a huge advance in the fight against cancer, exciting enough for him to postpone a planned move to Malaysia's burgeoning biotech community. The in situ approach is "very easy to reproduce" and inexpensive, "so it could be used in both developed and developing countries." Yet he retains a healthy cynicism. "I'm always a bit skeptical," he explains, "because we haven't made the translation" from mice to humans.

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