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Abstract:
MIT engineers have devised a way to deliver the necessary drugs by smuggling them within nanoparticles that are attached to the cells sent in to fight the tumor.

Nanoparticle-Decorated Cells Power Novel Approach

Bethesda, MD | Posted on September 20th, 2010

Clinical trials using patients' own immune cells to target tumors have yielded promising results. However, this approach usually works only when patients also receive large doses of drugs designed to help immune cells multiply rapidly, and those drugs have life-threatening side effects. Now a team of MIT engineers has devised a way to deliver the necessary drugs by smuggling them within nanoparticles that are attached to the cells sent in to fight the tumor. As a result, the immune cell stimulating drug reaches only its intended targets, greatly reducing the risk to the patient.

The new approach could dramatically improve the success rate of immune-cell therapies, which hold promise for treating many types of cancer, says Darrell Irvine. Dr. Irvine led the team that published its results in the journal Nature Medicine. "What we're looking for is the extra nudge that could take immune-cell therapy from working in a subset of people to working in nearly all patients, and to take us closer to cures of disease rather than slowing progression," said Dr. Irvine. The new method could also be used to deliver other types of cancer drugs or to promote blood-cell maturation in bone-marrow transplant recipients, according to the researchers.

To perform immune-cell therapy, doctors remove a type of immune cell called T cells from the patient, engineer them to target the tumor, and inject them back into the patient. Those T cells then hunt down and destroy tumor cells. Clinical trials are under way in which immune-cell therapy is being tested in patients with ovarian and prostate cancers, as well as melanoma.

Immune-cell therapy is a very promising approach to treating cancer, but getting it to work has proved challenging. The major limitations today include procuring enough of the T cells that are specific to the cancer cell and then getting those T cells to function properly in the patient. To overcome those obstacles, researchers have tried injecting patients with adjuvant drugs that stimulate T-cell growth and proliferation. The interleukins—naturally occurring chemicals that help promote T-cell growth—have produced promising results in human clinical trials, but interleukin therapy can produce severe side effects, including heart and lung failure, when infused into the blood stream in large doses.

Dr. Irvine and his colleagues took a new approach: To avoid toxic side effects, they turned to lipid-based nanoparticles that they can attach to sulfur-containing molecules normally found on the T-cell surface. The investigators loaded two interleukins - IL-15 and IL-21 - into the nanoparticles, and then injected the nanoparticle-T cell combo into mice with lung and bone marrow tumors. Once the cells reached the tumors, the nanoparticles gradually degraded and released the drug over a week-long period. The drug molecules attached themselves to receptors on the surface of the same cells that carried them, stimulating them to grow and divide.

Within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of interleukins died within 75 days.

Dr. Irvine and his colleagues also demonstrated that they could attach their nanoparticles to the surface of immature blood cells found in the bone marrow, which are commonly used to treat leukemia. Patients who receive bone-marrow transplants must have their own bone marrow destroyed with radiation or chemotherapy before the transplant, which leaves them vulnerable to infection for about six months while the new bone marrow produces blood cells. Delivering drugs that accelerate blood-cell production along with the bone-marrow transplant could shorten the period of immunosuppression, making the process safer for patients, says Dr. Irvine. In the Nature Medicine paper, his team reports successfully enhancing blood-cell maturation in mice by delivering one such drug along with the cells.

This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Therapeutic cell engineering with surface-conjugated synthetic nanoparticles." An abstract is available at the journal's Web site.

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