Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)

This is a non-randomized clinical trial of gene transfer using a self-inactivating, insulated, lentiviral gene transfer vector to treat 35 patients with X-linked severe combined immunodeficiency (XSCID, also called SCID-X1) who are between 2 and 50 years of age; who do not have a tissue matched sibling who can donate bone marrow for a transplant; who may have failed to obtain sufficient benefit from a previous half-tissue matched bone marrow transplant; and who have clinically significant impairment of immunity. A patient's own precursor cells (also called blood stem cells) that give rise in the marrow to blood and immune cells will have been or will be collected from the patient's blood or bone marrow. A patient will not proceed to gene transfer treatment in this protocol until there are at least 3 million blood stem cells per kilogram body weight collected from the patient. At the NIH the patient blood stem cells will be cells collected previously under NIH protocol 94-1-0073 or collected on this protocol. In most cases the harvested blood stem cells are put into frozen storage before use in this protocol. When the patient enrolled in this protocol has the required number of blood stem cells harvested, then the patient's blood stem cells will be grown in tissue culture and exposed to the lentiviral gene transfer vector containing the corrective gene. These gene-corrected blood stem cells will be administered through the patient's vein. To increase engraftment of the corrected blood stem cells, patients will receive a chemotherapy drug called busulfan at a total dose of 6 mg/kilogram body weight (3 mg/kilogram body weight/daily) for two days before the gene transfer treatment. The busulfan dose used in this study is a little more than one-third the dose used in many standard bone marrow transplants. To improve patient safety, those with significant organ damage may receive reduced busulfan dose of a total 4mg/kg with 2mg/kg dose given on Day 1, and dose adjusted on day 2 to achieve AUC of 6000 min*umol/L. Subjects who mobilize poorly (total CD34+ cells <5 million/kg) may use all their cells for product manufacture without leaving backup aliquot of 1e6/kg.

For patients who have clinical problems related to donor T cell dysregulation, alemtuzumab (Campath) may be administered. Patients will also be given another drug called palifermin that helps prevent the main side effect from the busulfan, which is a type of inflammation of the mouth, stomach and bowels called mucositis. After the gene transfer treatment, patients will be monitored to see if the treatment is safe and whether their immune system improves. Patients will be followed at frequent intervals for the first 2 years, and less frequently thereafter so that the effectiveness in restoration of immune function and the safety of the treatment can be evaluated.

XSCID is a genetic disease caused by defects in common gamma chain, a protein found at the surface of immune cells called lymphocytes and is necessary for their growth and function. XSCID patients cannot make T-lymphocytes necessary to fight infections, and their B-cells fail to make essential antibodies. Without normal T- and B-lymphocyte function, patients develop fatal infections in infancy unless they receive a bone marrow transplant from a healthy donor. The best type of transplant is from a tissue-matched healthy brother or sister, but most XSCID patients do not have a tissue-matched sibling and are treated with a transplant from a parent who is only half- matched by tissue typing. While a half-matched transplant from a parent can be lifesaving for an infant with XSCID, a subset of patients fails to achieve sufficient long lasting restoration of immunity to prevent infections and other chronic problems. Trials of gene transfer treatments using mouse retrovirus vectors for infants with XSCID have been performed and have demonstrated that this type of gene transfer can be an alternate approach for significantly restoring immunity to infants with XSCID. However, among the 18 infants with XSCID benefiting long-term from the gene transfer treatment, 5 developed Tlymphocyte leukemia and 1 died of this leukemia. Furthermore, when older children with XSCID were treated with gene transfer, the restoration of immunity was much less than seen in the infants. These observations of gene transfer treatments using mouse retrovirus vectors to treat infants and older patients with XSCID suggest that safer and more effective vectors were needed, and that there also may be a need to give chemotherapy or other method of conditioning to increase engraftment in the marrow of the gene corrected blood stem cells. Our data and other published studies suggest that lentivectors that are derived from the human immunodeficiency virus and have the properties of our highly modified vector called CL20-4i-EF1alpha- h-gamma-c-OPT have a reduced interaction with nearby genes and therefore less of a tendency to activate genes that may lead to cancer formation. Also, this type of lentivector may work better at getting into blood stem cells.

The purpose of this study is to evaluate the safety and effectiveness of the lentiviral gene transfer treatment at restoring immune function to XSCID patients who are 2 to 50 years of age and have significant impairment of immunity. Early evidence for effectiveness will be defined by appearance and expansion in the circulation of the patient's own gene corrected T-lymphocytes with a functional gamma-c gene and improved laboratory measures of immune function. The primary endpoint for efficacy will be assessed 2 years after treatment and will include these laboratory parameters plus evidence for clinical benefit. Evidence for safety will focus on the maintenance of a diversity of gene marked cells and no occurrence of abnormal patterns of production of blood cells or any leukemia or other cancer. The primary study endpoints for all laboratory and clinical measures of efficacy and safety will occur at 2 years after gene transfer treatment. However, data collection regarding efficacy will occur at frequent intervals during the 2 years leading up to the endpoint analysis, through study completion at 5 years. Safety and efficacy evaluations will continue yearly under a separate NIH study during the long-term follow-up period recommended by the United States FDA for patients participating in gene transfer treatment studies.