BioWorld International Correspondent

LONDON - Transplants of stem cells engineered to carry genes that confer resistance to chemotherapeutic drugs could be used to treat patients with lymphomas and leukemias within a decade. Researchers in the UK say their work in mice already has proved that the strategy can work.

Raj Chopra, group leader at the Paterson Institute in Manchester, UK, told BioWorld International, "This work has many implications beyond bone marrow transplantation. If we can give donor stem cells - which are never going to be in abundant supply - an advantage in some way, this allows us to use limited numbers of stem cells to carry out various types of tissue engineering."

Applied to hematological malignancies such as lymphomas and leukemias, the technique involves engineering a protective gene into bone marrow stem cells before using those to replace the patient's cells. As a result, the donated cells become capable of surviving subsequent chemotherapy, while host bone marrow stem cells, including tumor cells, succumb.

Chopra described the technique at the first annual conference of Cancer Research UK, the UK's largest cancer research charity, held last week in Kenilworth. The proposed strategy, which he said is likely to take five years to refine before it can be used on patients, builds on work that the group has recently completed on an improved treatment for leukemias and lymphomas.

Known as "minitransplants," this type of therapy is aimed at reducing the risk of graft-vs.-host disease (GVHD), which can kill up to 40 percent of people who undergo a bone marrow transplant during treatment for leukemia or lymphoma. GVHD results from an immunological reaction in which donor cells attack host cells as foreign, exacerbated by the response of the individual's immune system to the high-dose radiotherapy received prior to the transplant.

To avoid GVHD, the minitransplant schedule involves giving an immunosuppressive antibody, called Campath, to patients before the transplant. Campath blocks a cell-surface protein called CD52, which is found on T cells, monocytes and macrophages, thus inhibiting the immune response.

In a paper published last month in the Journal of Clinical Oncology, titled "Role of Nonmyeloablative Allogeneic Stem-Cell Transplantation After Failure of Autologous Transplantation in Patients With Lymphoproliferative Malignancies," Chopra and his colleagues described how the strategy improved survival rates for patients with advanced Hodgkin's disease and non-Hodgkin's lymphoma. When they treated 38 such patients, they found that 53 percent survived another 14 months when, without transplants, they would have been expected to survive only 10.5 months on average in the case of advanced Hodgkin's disease, and three months with advanced non-Hodgkin's lymphoma.

The group hopes to improve the survival rates yet further with its strategy of first inserting a protective gene into the donor stem cells. The gene concerned encodes an enzyme called atase, a naturally occurring enzyme that has the role of repairing DNA breaks and cross-linking. A retrovirus was used to insert the gene.

"If you give chemotherapeutic drugs, which are alkylating agents, these cause breaks in the DNA or make cross-links with the DNA, leading to the death of the cell. If atase is present, it can repair these abnormalities in the genetic material of the cell," Chopra said. "So when the disease starts coming back, we can give chemotherapy, which will knock out the host cells, including tumor cells, while the donor cells will survive and the graft can therefore take hold. We have done this in mouse models of leukemia and lymphoma, and shown that it works."

He and his colleagues are now working on ways of infecting human stem cells in the laboratory with their genetically engineered retrovirus.

In a separate presentation at the Kenilworth conference, Ron Laskey, honorary director of the Medical Research Council's Cancer Cell Unit in Cambridge, described the results of a small trial to evaluate a new screening test for bowel cancer. The test looks for the presence of a molecule called MCM2, which is involved in making new DNA and is present only in cells that are actively dividing, such as cancerous or precancerous cells. (See also "Urine test for bladder cancer could detect prostate cancer" in BioWorld International, July 24, 2002.)

Researchers tested the feces of two groups of people, those with bowel cancer and healthy volunteers. In the patient group, 37 out of 40 tested positive for MCM2, whereas the molecule was not detected in any of the healthy individuals.

Laskey said MCM2 looked like an "exceptionally promising way" of improving diagnosis, not only for bowel cancer but for other forms of cancer, too. "However, we still need to do larger-scale studies on the new test and, in particular, we need to examine its effectiveness in people with very early, presymptomatic bowel cancer," he said.

Cancer Research UK believes the new fecal test might work well alongside sigmoidoscopy for screening for bowel cancer. Robert Souhami, director of clinical research at the charity, said neither fecal tests nor internal examinations would pick up every case of cancer, but the two methods together could prove highly effective in reducing mortality.