New approach to targeted therapy--on the backs of t-cells!!!

[Lani]

A pharmacy on the back of a cell: Drugs encapsulated in new MIT nanoparticles can hitch a ride to tumors on the surface of immune-system cells
[MIT]

Clinical trials using patients' own immune cells to target tumors have yielded promising results. However, this approach usually works only if the 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 on the backs of the cells sent in to fight the tumor. That way, the drugs reach only their 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, senior author of a paper describing the technique in the Aug. 15 issue of 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," says Irvine, associate professor of biological engineering and materials science and engineering and a member of MIT's David H. Koch Institute for Integrative Cancer Research.

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.

T-cell therapy

To perform immune-cell therapy, doctors remove a type of immune cells 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 for ovarian and prostate cancers, as well as melanoma.

Immune-cell therapy is a very promising approach to treating cancer, says Glenn Dranoff, associate professor of medicine at Harvard Medical School. However, getting it to work has proved challenging. "The major limitation right now is getting enough of the T cells that are specific to the cancer cell," says Dranoff, who was not involved in this study. "Another problem is getting 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. One class of drugs that has been tested in clinical trials is interleukins — naturally occurring chemicals that help promote T-cell growth but have severe side effects, including heart and lung failure, when given in large doses.

Irvine and his colleagues took a new approach: To avoid toxic side effects, they designed drug-carrying pouches made of fatty membranes that can be attached to sulfur-containing molecules normally found on the T-cell surface.

In the Nature Medicine study, the researchers injected T cells, each carrying about 100 pouches loaded with the interleukins IL-15 and IL-21, into mice with lung and bone marrow tumors. Once the cells reached the tumors, the pouches gradually degraded and released the drug over a weeklong 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.

The study was funded by the National Institutes of Health, the National Science Foundation, the National Cancer Institute and a gift to the Koch Institute from Curtis '63 and Kathy Marble.



ABSTRACT: Therapeutic cell engineering with surface-conjugated synthetic nanoparticles
[Nature Medicine]

A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.