November 4, 2004 /PSA Rising/ Texas. - A delivery system for anticancer treatment that zeroes in on a tumor and becomes part of its supporting tissue is under development at M. D. Anderson Cancer Center. This new "cellular vehicle" uses engineered stem cells to pump drugs directly into cancer cells to disable them, but leaves normal tissue alone.
The researchers say their study, published in the Journal of the National Cancer Institute, is a proof of principle, conducted in mice, that shows this kind of strategy could be promising when developed for human use.
"This is the most effective homing strategy seen to date, much better than any viral delivery strategy tested so far," says Michael Andreeff, M.D., Ph.D , professor in the Departments of Blood and Marrow Transplantation and Leukemia. "It is remarkable that these cells can find tumors wherever they are and become part of them." [continued]
Figure 1. Strategies for Delivering Therapeutic Transgenes into Patients.
(© 2001 Terese Winslow)
The new approach uses human mesenchymal stem cells (MSC), the body's natural tissue regenerators. Tissue that is injured sends signals to these unspecialized, progenitor cells, and they, in turn, migrate to the damage and morph into whatever kind of tissue -- bone, fat, muscle, cartilage, tendons -- is needed to repair the wound.
Tumors, however, are "never-healing wounds" that also signal these stem cells, and then use them to help build up "stromal," or connective tissue, that structurally supports and nurtures tumor growth, says Andreeff. "Tumors constantly remodel their architecture with the help of these special stem cells."
Andreeff, first author Matus Studeny, M.D., who was a research fellow in Andreeff's lab, and a group of six other researchers turned the tables on cancer, taking advantage of a tumor's ability to attract these stem cells.
They designed a novel delivery system by isolating a small quantity of MSC from bone marrow, and then greatly expanded those cells in the lab. The researchers then used a virus to deliver a particular gene that has therapeutic action against cancer into the stem cells. When given back through an intravenous injection, the millions of engineered mesenchymal progenitor cells engraft where the tumor environment is signaling them, and then activate the therapeutic gene.
This system has been tested in a number of different solid cancers, as well as in leukemia, to deliver different "payloads," but in this study, the team looked at whether MSC engineered to carry interferon beta could treat mice that were implanted with human breast cancer or human melanoma.
Interferon beta can inhibit cancer growth in laboratory tests, but is excessively toxic and short-lived when used at high doses as a therapy in patients, says Andreeff. The team tested whether MSC engineered to express an interferon beta gene could provide a sustained and targeted effect directly to cancer cells.
For each of the two cancer types, the researchers tested three groups of mice against each other: one was an untreated control group; another was injected with interferon beta daily under the skin for three weeks; and the third received three weekly doses of intravenous MSC engineered to express the interferon beta payload.
They found that the MSC cellular vehicles readily grafted themselves into the tumor stroma and proliferated. The cells also delivered its drug over a long period of time, significantly improving survival of the mice.
Specifically, mice whose breast cancer was treated with MSC survived 60 days compared to 41 days in the mice injected with interferon beta, and 37 days in untreated mice. Mice with melanoma that were treated with MSC more than doubled their survival (73.5 days) compared with treated mice (32 days) and untreated mice (30 days).
Andreeff says that use of interferon beta therapy in this study is less important than proof that the MSC strategy works. "The most important discovery here is that these cells are indeed homing into tumors and are capable of delivering an anticancer payload,"he says. "Now we can work to test a number of different therapeutic payloads to see which works best."
He speculates that this new tactic in the war on cancer might work particularly well after patients are treated with radiation or chemotherapy, because those therapies damage cancer cells, which would then be in critical need of MSC. Andreeff hopes that this new homing strategy might offer a novel way to treat cancer that has spread. "This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," he says.
The study was supported by the National Cancer Institute, the Public Health Service, the Stringer Professorship for Cancer Treatment and Research, and the W. M. Keck Foundation. Researchers who participated in the study are Frank Marini, Ph.D., Jennifer Dembinski, Claudia Zompetta, Maria Cabreira-Hansen, Ph.D., Benjamin Nebiyou Bekele, Ph.D., and Richard Champlin, M.D.
Page edited by J. Strax, Oct 23, 2004
