DALLASUniversity of Texas M.D. Anderson researchers plan to
test whether removal of residual breast cancer cells from stem cell
transplant grafts will improve the long term success of such
transplants for patients with late-stage metastatic breast cancer.
Such patients currently have quick relapse of the cancer after
high-dose chemotherapy with stem cell support. However, none of the
transplant studies reported to date used grafts that were fully
devoid of tumor cells, said Frank Marini, PhD, of the Section of
Molecular Hematology and Therapy, Department of Blood/Marrow Transplant.
We have created a novel breast cancer purging technique by
combining two independent eradication strategies, said Dr.
Marini, who presented his work at the Susan G. Komen Foundation
National Grants Conference (Reaching for the Cure: The Next Step).
At M.D. Anderson, he said, patients are transplanted only on clinical
trials. It appears promising in patients with local breast
cancer (stages II and III) with high-risk features and in patients
with chemotherapy-responsive metastatic disease, he said. There
were 100 breast cancer transplants in 1998 at M.D. Anderson, and 61
such transplants in 1999.
The eradication strategy includes specific enrichment of stem cell
progenitor CD34+ cells in the graft by magnetic antibody separation
purification via the ClinicMACS device (Miltenyi Biotec/Amcell). This
is followed by infection of the enriched stem cells by a recombinant
adenoviral vector that preferentially infects contaminating breast
cancer cells but not hematopoietic cells (see Figure).
Using these two techniques together, we can reduce the number
of contaminating breast cancer cells by 5 to 7 logs, thereby
providing a graft free of tumor, Dr. Marini said.
The magnetic antibody separation device uses antibodies that bind to
stem cells and selects them in a magnetic column.
For adenoviral virus purging, the researchers generated a recombinant
adenovirus carrying the bifunctional protein GAL-TEK (known as
adGAL-TEK). Cells infected with adGAL-TEK are forced to commit
suicide by the addition of the prodrug ganciclovir [Gemzar],
Dr. Marini said.
A clinical trial is planned using the combined enrichment/purging
technique in 10 to 12 women with late-stage breast cancer and
histologic evidence of disease in blood and bone marrow. The protocol
is currently under review by the institutions IRB.
We will assess whether our genetic purging strategy is safe and
effective for removing contamination and whether it has any impact on
the quality of the stem cell graft, Dr. Marini concluded. His
colleagues in the study are Drs. V. Snell, R. Champlin, and M.
Andreeff, in collaboration with S. Eva Singletary, MD, Surgical
Breast Oncology, and Gabriel Hortobagyi, MD, Breast Oncology.