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P&S Journal

P&S Journal: Fall 1994, Vol.14, No.3
Research Reports
Columbia's First Gene Therapy Trial

P&S researchers are taking their first steps in the long process of developing a new therapy to protect cancer patients from the toxic effects of chemotherapy by genetically modifying bone marrow cells. The gene-based technology under study also might treat hemoglobinopathies and other diseases someday.
For now, however, the goal of this phase I trial approved by the FDA, the NIH's Recombinant Advisory Committee, and CPMC's internal reviewers is to determine if bone marrow cells can be genetically altered and, if so, how patients are affected by the procedure.
The team is led by Dr. Charles Hesdorffer, assistant professor of clinical medicine; Dr. Karen Antman, professor of medicine; and Dr. Arthur Bank, professor of medicine and of genetics and development.
The scientists will put a potentially useful gene into a CD-34+ hematopoietic stem cell-containing fraction of bone marrow cells-as the cells are nourished with growth factors-from 20 patients with advanced breast, ovarian, or brain cancer. CD-34+ hematopoietic stem cells produce blood components such as red and white blood cells and platelets. The investigators will put the gene-the multidrug resistance (MDR) gene-into the cells using a safe, defective retrovirus engineered to express MDR at high levels. The MDR retrovirus is being provided by Genetix Pharmaceuticals Inc., a New York-based biotechnology company that licensed the technology from Columbia. The MDR gene product pumps harmful substances, including chemotherapeutic agents such as taxol or doxorubicin, out of cells, inactivating them. Normally bone marrow cells have low MDR expression and thus are susceptible to these drugs' toxic effects.
After the in vitro gene transfer, the scientists will reinfuse both MDR-modified and unmodified CD-34+ cells into patients pre-treated with high-dose chemotherapy.
The theory behind the Columbia gene therapy strategy is that if bone marrow stem cells produce higher levels of MDR as a result of the introduction of the new gene, they and progeny cells could survive standard or even higher doses of chemotherapy. Patients with such genetically altered stem cells may then be protected from bone marrow toxicity that normally accompanies cancer drug treatment.
Published work by Dr. Bank's laboratory has validated this hypothesis in live mice. Dr. Bank transferred the MDR gene into mouse bone marrow and found that after transplantation and subsequent taxol treatment, MDR+ cells circulated in peripheral blood.
Although this phase I trial may provide information about whether genetically modified bone marrow can withstand chemotherapy after transplantation, the study's primary purpose is to determine if the MDR gene can be inserted into human hematopoietic cells and to monitor the safety in human patients. For such therapy to be useful, the researchers must first show the presence and expression of the MDR gene in bone marrow and blood weeks and months after marrow reinfusion. They will use Southern blots and PCR to detect the MDR gene and FACS to measure MDR on cell surfaces. Marrow is expected to re-engraft three to four weeks after infusion, when genetically modified progeny cells in peripheral blood should be detectable. Delayed engraftment or a second malignancy due to the retroviral gene transfer are potential side effects.
If bone marrow MDR gene therapy proves successful, patients would require fewer hospitalizations for infections or bleeding, common side effects of chemotherapy, and may be able to receive higher doses of drugs in their treatment. Today, high-dose chemotherapy is being evaluated for various forms of advanced cancer. Candidates for the Columbia study are patients eligible for protocols using high-dose chemotherapy and bone marrow support.
Pending results from these trials, the researchers also plan to put the MDR gene into peripheral blood (PB) stem cells, which also can repopulate human marrow. PB stem cells can be harvested from the blood in an outpatient setting without the discomfort of marrow aspirations or hospitalization. MDR-treated PB stem cells could be given repeatedly and for less advanced cancers.
MDR gene therapy also could be applied to treat other illnesses. To treat sickle cell anemia, for example, in which patients have a defective hemoglobin gene, a retrovirus with both the MDR and hemoglobin genes could be devised. If a patient were infused with marrow altered to contain the two genes and then exposed to low-dose chemotherapy, cells selected to contain both genes could repopulate the marrow to produce red blood cells with "normal" hemoglobin.
- Robin Eisner


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