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Particles that Train T-Cells

The human immune system needs some schooling. That’s according to Tarek Fahmy, a Yale University biomedical engineer. He says people with cancer have a shortage of “educated” T-cells, which recognize and destroy tumor cells. Now, he and graduate student Erin Steenblock are developing particles that boost T-cell counts.

In a study published in the journal Molecular Therapy, Fahmy and Steenblock used blood from mice to show that their particles generate an increase in tumor-fighting T-cells. “The cells expand like crazy when they see these particles,” says Fahmy. “It’s a very good way to expand their number,” he says.

Because of the particles’ adjustable design, they could also be adapted to help restock the T-cells that fight viruses such as HIV or the flu. “This work can begin to make basically a drug, a formula, a powder that can actually be used in the clinic with physicians to help boost the immune responses against some of these infectious diseases as well as against tumors,” he says.

Fahmy says that luckily, cytotoxic T-cells, or killer T-cells, were the type of T-cells that proliferated in his study. But details of how the particles specifically boost cytotoxic T-cell numbers remain a mystery. “How they’re doing it, we have no idea. We don’t know why they expand that specific subtype population,” he explains. “It’s a fortuitous discovery,” says Fahmy.

Fahmy and Steenblock’s material, which looks like baking powder, is made up of individual particles smaller than human cells. The tiny shell of each particle is made of a familiar compound, it’s the same stuff used to make the dissolvable sutures that surgeons use to tie up our vital organs.

Once the particle shells are made, the next step is to “decorate the surface of these really small, small particles with molecules that recognize T-cells,” he says. These decorative surface molecules cause the body’s own T-cells to stick to the particles.

Once they latch on to the T-cells, the particles dissolve and release certain natural chemicals, called cytokines. Studies have shown that cytokines help tell T-cells to proliferate. But cytokines may be toxic when taken in the large doses. With Fahmy and Steenblock’s new particles, cytokines get delivered directly to a patient’s T-cells. If the particles make it to the clinic, patients could benefit from new T-cells without having to take a toxic dose of cytokines.

In their recent study, Fahmy and Steenblock tested their powder in what’s called an ex vivo, literally, out of body approach. The researchers took samples of mouse blood, ditched all but the T-cells, and sprinkled in their powder. After incubating the particles with the original T-cells for an hour, the researchers checked in their electron microscope. Sure enough, the particles and the T-cells coupled up.

Fahmy and Steenblock also tracked the T-cells as they multiplied. Fahmy says that for every T-cell that links to a particle, 40 new T-cells will develop within days. “And so take that and multiply it by millions, because initially millions of cells see these particles,” Fahmy explains, and you’ve got a big army of trained T-cells ready to attack tumors.

If the T-cell boosting powder becomes available, cancer patients potentially could donate their own blood, have it incubated with the powder, and have their restocked T-cells re-infused back into their bodies. In general, this so-called adoptive immunotherapy approach already has shown promise, but Fahmy and Steenblock’s work could advance the field. “Adoptive immunotherapy has been limited by the types, the numbers” of T-cells researchers can generate, says Fahmy. “There’s been really no good technology that allows you to do that,” he says.

Although the immune system is capable of some impressive feats, tumors unfortunately can escape its notice. In people with malignant tumors, cancer cells “fool the body in thinking they are actually part of the body itself,” Fahmy says. If unchecked by the immune system, cancer cells divide and spread, causing disease. At that point, it’s time “to try and intervene, and try to reeducate the immune system and help it. Try to get it to fight those cancer cells that are increasing in number,” says Fahmy.

Fahmy’s particles are made of FDA-approved materials like poly(lactide-co-glycolide), the degradable suture compound. That means if future trials are successful, they potentially could be injected directly to expand T-cell numbers. So Fahmy predicts that in the long-term, “there will be no need to go through a separate step where you draw blood, expand, and then reinfuse back into the person.” But for now, Fahmy and Steenblock are in the midst of new animal trials to determine whether the new supply of smart T-cells really can help battle cancer. So far, Fahmy says, results are “very promising.”

The researchers’ work was published in the February 26, 2008 advance online edition of Molecular Therapy. It was funded by the National Science Foundation, and the U.S. Department of Homeland Security.

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