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Novel gene therapy delivery uses stem cells that target, attack tumors

09.12.2003


Genetically engineered stem cells can find tumors and then produce biological killing agents right at the cancer site, say researchers at The University of Texas M. D. Anderson Cancer Center, who have performed a number of successful "proof of concept" experiments in mice.



Their novel treatment, presented at the annual meeting of the American Society of Hematology (ASH), may offer the first gene therapy "delivery system" capable of homing in on and then attacking cancer that has metastasized -- wherever it is in a patient’s body. And the stem cells will not be rejected, even if they are not derived from the patient.

The researchers have tested the system in mice with a variety of human cancers, including solid ones such as ovarian, brain, breast cancer, melanoma and even such blood-based cancer as leukemia. "This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," says Michael Andreeff, M.D., Ph.D., professor in the Departments of Blood and Marrow Transplantation and Leukemia. "We believe this to be a major find."


M. D. Anderson has filed patent applications on the system, which uses human mesenchymal progenitor cells (MSC), the body’s natural tissue regenerators. These unspecialized cells can migrate to an injury by responding to signals from the area. There they develop the kind of connective tissue that is needed to repair the wound, and can become any kind of tissue required.

Tumors are "never-healing wounds" which use mesenchymal stem cells to help build up the normal tissue that is needed to support the cancer, says Andreeff. "There is constant remodeling of tissue in tumors," he says. So researchers turned the tables on the cancer, taking advantage of a tumor’s ability to attract the stem cells.

In their novel delivery system, researchers isolate a small quantity of MSC from bone marrow, and greatly expand the quantity of those cells in the lab. They then use a virus to deliver a particular gene into the stem cells. When turned on, this gene will produce an anti-cancer effect. When given back to the patient through an intraveneous injection, the millions of engineered mesenchymal progenitor cells will engraft where the tumor environment is signaling them, and will activate the therapeutic gene.

In the study reported at ASH, the researchers examined whether MSC producing human interferon-beta can inhibit the growth of metastatic tumors in the lungs of mice that do not have a functioning immune system. They used an adenovirus vector to deliver the gene that expresses interferon-beta, which can prevent cell reproduction. Andreeff and his team found that when mice were treated with just four weekly injections, their lifespan doubled, on average. They also discovered that when treated cells were placed under the skin of the mice, there was no effect. "The cells need to be in the immediate environment of the tumor to work," which suggests that normal tissue will not be adversely affected, says Andreeff.

Other studies being reported by Andreeff that used different therapeutic "payloads" found a doubling of survival in mice with one kind of ovarian cancer and a cure rate of 70 percent in mice with a different kind of ovarian tumor. Another study demonstrated that when the gene therapy was injected into the carotid (neck) artery of mice with human brain cancer, the genes incorporated themselves into the cancer, not into normal brain tissue.

Further work suggested the novel therapy may be able to help treat resistant blood cancers. Delivery of the interferon-alpha gene product helped destroy leukemia cells, Andreeff says.

"These results suggest that gene-modified MSC can inhibit the growth of leukemias, metastatic tumors of the lungs, and ovarian and brain tumors," he says. "We will need to optimize the genes that are delivered, but the most important discovery here is that these cells are capable of migrating from the bone marrow or blood circulation into tumors, and suggests this can be developed into a potent therapy."


Contact: Julie Penne, 713-792-0655; jpenne@mdanderson.org
Laura Sussman, 713-792-0655; lsussman@mdanderson.org

Julie Penne | EurekAlert!

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