In an advance online article in the journal Molecular Therapy, researchers from Yale University described what amounts to an artificial dendritic cell: a biodegradable antigen-presenting system that mimics three of the major ways in which dendritic cells and T cells interact with each other, and dramatically increases the expansion of harvested T cells. The findings could provide a method to improve the strength of T-cell-based vaccines.

In cancer treatment as well as infectious diseases, harnessing T cells in a so-called adoptive immunity strategy "could potentially have widespread use," senior author Tarek Fahmy told BioWorld Today. "But it's been limited by a number of factors, and one of them is antigen presentation."

T-cell-based vaccines potentially could rival monoclonal antibodies in their impact on cancer treatment. If only they could hit their endpoints. So far, approaches based on T-cell stimulation have failed to gain FDA approval. (See BioWorld Today, Dec. 26, 2007, and May 10, 2007.)

Although overactive T cells led to problems in at least one clinical trial, the problem, by and large, is the opposite: T-cell responses are not sufficient to provide clear evidence of clinical efficacy, at least not to the point of convincing the FDA.

The root of the problem appears to be not even so much the T cells themselves as the dendritic cells used to stimulate them, which, Fahmy said, "are hard to come by" in the amounts needed to sufficiently rev up T cells. To get T cells into gear, dendritic cells actually do three things: They stimulate the recognition receptor on the T cell with the antigen itself; they activate T cells via the so-called co-stimulation pathway; and they secrete cytokines, which enhances T-cell proliferation even more.

The basic goal, Fahmy said, was "to create an off-the-shelf system by recapitulating those three functions artificially." And that is what he and first author Erin Steenblock did, using biodegradable microparticles from a material commonly used for sutures, turning them into vesicles that can release cytokines slowly, and studding them with antigens and costimulatory molecules.

When they used the artificial cells to stimulate T cells, the cells expanded up to 45-fold within a week compared to unstimulated T cells. Fahmy said that he and Steenblock made "two key discoveries" with and about their system.

For one, to achieve good T-cell expansion, "the cytokine needs to be delivered in a local fashion" rather than added to the culture medium. Why that is the case is not entirely clear yet, but Fahmy said that it probably allows high local concentrations of cytokine in the vicinity of the T cell.

Secondly, in a finding that Fahmy called "flabbergasting," for some reason, the artificial dendritic cell makes it more likely that proliferating T cells will turn into CD8-positive or killer T cells. Killer T cells "are extremely important for anticancer activity, because they basically kill cancer cells on contact," Fahmy said; and stimulation with the artificial system leads to a T-cell population that is made up of nearly 95 percent CD8 cells. "We don't know why yet, but that's what we're seeing," Fahmy said.

For now, the work presented is completely in vitro. Fahmy and his team currently are testing the activated T cells in animal tumor models. Fahmy declined to discuss the data in advance of their peer-reviewed publication, but said that the results so far had been "remarkable."

He said he hopes that the artificial system eventually will provide an easier way to stimulate T cells than autologous dendritic cells do. Eventual clinical applications, Fahmy said, "probably would involve in vivo administration of these particles."