NIH Researchers Use Cell Selection to Engineer Success With Mini Transplant Treatment for Rare Blood Disorder
IRVINE, Calif.--(BW HealthWire)--Dec. 7, 1999--
Eight of Nine Patients Achieve Functioning, Chimeric Immune
Systems From Sibling Stem Cell Grafts
Researchers at the National Institutes of Health (NIH) have successfully corrected a rare blood disorder, chronic granulomatous disease (CGD), using a mini transplant conditioning regimen incorporating Isolex(R) stem cell selection technology to purge donor T-cells from the stem cell graft. This approach reduced both conditioning related toxicity and the severity of graft versus host disease (GVHD), which have limited the utility of donor stem cell transplantation in the treatment of inherited blood disorders. Initial data from a study of nine CGD patients were presented today in New Orleans, Louisiana, at the Annual Meeting of the American Society of Hematology by Mitchell E. Horwitz, MD, of the National Institute of Allergy and Infectious Diseases, part of the NIH.
Over 1,000 Americans and more than 25,000 individuals worldwide suffer from CGD, caused by a gene mutation that prevents white blood cells called neutrophils from generating hydrogen peroxide, their main weapon against bacteria or fungi. With their immune systems unable to kill foreign organisms, CGD patients suffer from frequent, often life-threatening infections of the skin, lungs, liver and bones. As a result, most people with the disorder succumb to infection and may not live beyond their twenties or thirties.
Previous studies have suggested that transplanting stem cells from a closely matched relative can provide the CGD patient with a functioning immune system if the proportion of donor neutrophils can be maintained at 10 percent or more over time. The goal is to give the patient an immune system populated with a stable number of donor stem cells and their cellular progeny, a state called chimerism. However, standard donor (or allogeneic) transplants present significant challenges because of the toxicity of the chemotherapeutic regimens traditionally used to ablate the host's defective immune system prior to transplant and the propensity of donor T-cells in the graft to attack the host, a condition called graft versus host disease (GVHD). Because it is ultimately donor-derived T-cells in a mini transplant that both eliminate the abnormal host blood cells and cause GVHD, a delicate balance has to be struck between engrafting too many T-cells (causing GVHD) and too few (contributing to failure of donor cell engraftment).
In the NIH study, investigators addressed these issues by using low-intensity, and therefore less toxic, chemotherapeutic conditioning (cyclophosphamide 60mg/kg x2, fludarabine 25 mg/mE2 x5, anti-thrombocyte globulin 40mg/kg x4) and by using the investigational Isolex(R) 300i Magnetic Cell Selection System for positive/negative selection to perform simultaneous positive CD34+ stem cell selection and T-cell depletion on the peripheral blood stem cell (PBSC) graft. Importantly, cell selection allowed the investigators to standardize the dose of T-cells given to each patient in the initial graft at 1 x 10E5 CD3+ cells/kg. Selection with the Isolex(R) 300i was performed in the Cell Processing Center established within the Department of Transfusion Medicine at the NIH Clinical Center under a Cooperative Research and Development Agreement (CRADA) with Nexell.
Nine patients, ranging in age from five to thirty seven years old, were given the conditioning regimen and eight were successfully transplanted with the T-cell depleted PBSC grafts. Patients were given additional donor lymphocyte infusions on day 30 and day 60 if they were less than 60 percent donor T-cell chimeras. Patients were also given cyclosporine for 100 days. The conditioning regimen was well tolerated with no significant toxic side effects observed. Two cases of GVHD (Grade III skin) were observed. The GVHD was transient in one patient, but became chronic in another who was unable to tolerate the full treatments with cyclosporin due to preexisting renal dysfunction. At greater than 100 days follow-up, eight of nine patients have established donor stem cell chimerism. Seven of these patients have surpassed the 10 percent donor neutrophil threshold (three of which are at 100 percent donor neutrophils), thus establishing immune competence. The eighth engrafted patient has 7 percent donor neutrophils and this value appears to be increasing.
The researchers concluded that because they had successfully decreased conditioning related toxicity and the severity of GVHD, this approach to allogeneic stem cell transplantation may be ideal for treatment of CGD as well as other non-malignant stem cell and blood cell based disorders.
As previously announced, the NIH research group has also demonstrated successful production of oxidase normal neutrophils in the peripheral blood of CGD patients treated with gene therapy facilitated by Nexell cell selection and expansion technologies. This gene therapy approach is being investigated for patients who lack a matched related stem cell donor.
The Isolex(R) 300i Magnetic Cell Selection System is approved by the U.S. Food and Drug Administration as a restricted device for the selection of hematopoietic stem cells and the removal of tumor cells from autologous peripheral blood grafts used to restore cancer patients' immune and blood-forming systems following high dose chemotherapy. It is the only stem cell selection system commercially available in the United States. The Isolex(R) 300i System package insert contains complete prescribing information.
The Isolex(R) 300i System capable of positive/negative selection used in this study is currently only commercially available in Europe. This system may be used in the United States under Investigational Device Exemption (IDE) only. Such IDE's have been granted for investigational protocols with the Isolex(R) in gene therapy and dendritic cell therapy, engineered transplants with alternative donors and for autoimmune diseases.
Nexell Therapeutics Inc. |
