Bethesda, Maryland 20892


Background: - X-linked severe combined immunodeficiency (XSCID) is caused by a genetic abnormality in the IL2RG gene that affects the growth and development of immune cells such as white blood cells. Individuals with XSCID have difficulty fighting infections, which may lead to chronic or severe illness and death. The primary treatment for XSCID is replacement of the patient s immune system with a normal immune system through a bone marrow transplant. The best outcomes in transplant patients are achieved when the bone marrow comes from a sibling, but parents and matching unrelated donors can provide bone marrow for transplant as well. However, because these transplant procedures are not always effective, researchers are studying gene transfer treatment as an approach to treating XSCID. - Lentiviral gene transfer treatment uses good genes to replace defective genes. A lentivirus is a virus that has been modified to carry corrected genes into the blood through corrected stem cells. By collecting an individual s stem cells and modifying them with a lentivirus, the gene-corrected cells can be returned into the blood to help produce normal healthy immune cells. Gene transfer treatment with lentivirus vector has been used in humans but has never been studied in patients with XSCID. Objectives: - To determine the safety and effectiveness of lentiviral gene transfer as a treatment for children and adolescents with X-linked severe combined immunodeficiency. Eligibility: - Children and adolescents between 2 and 20 years of age who have XSCID related to a defect in the IL2RG gene and who are not currently under treatment with strong immune-modulating or chemotherapy drugs. Design: - Participants will be screened with a medical history, physical examination, blood and urine tests, and bone marrow samples to collect stem cells for the procedure. - Participants will be admitted to the National Institutes of Health Clinical Center 11 to 12 days before receiving gene-corrected blood stem cells. - Participants will receive palifermin for 3 days, followed by busulfan for 2 days. Palifermin will help prevent side effects from busulfan, and busulfan will help suppress the immune system in preparation for the gene transfer. Participants will have regular blood tests during this preparation period. - Participants will receive a transfer of their corrected blood stem cells about 36 to 48 hours after the second dose of busulfan. The cells will be injected over 5 to 10 minutes under close monitoring. - The day after the transfer, participants will have 3 more days of palifermin. - Participants will remain in the hospital for several weeks, possibly as long as 6 weeks, while the response to treatment is monitored. - Participants will continue to be monitored for immune function and possible side effects after leaving the hospital, and will be followed for up to 15 years after the procedure to evaluate the long-term effects of gene transfer therapy. The monitoring will involve regular physical exams and blood samples.

Study summary:

This is a non-randomized clinical trial of gene transfer using a self-inactivating, insulated, lentiviral gene transfer vector to treat 13 patients with X-linked severe combined immunodeficiency (XSCID, also called SCID-X1) who are between 2 and 40 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 collected from either the blood or bone marrow under another protocol (NIH protocol 94-1-0073 or a successor approved protocol) that is specific for collection of such cells. 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 by vein to the patient. To increase engraftment of the corrected blood stem cells, patients will receive on 2 days before the gene transfer treatment a chemotherapy drug called busulfan at a total dose of 6 mg/kilogram body weight (3 mg/kilogram body weight/daily times 2 days) that is a little more than one-third the dose used in many standard bone marrow transplants. Patients will also be given another drug called palifermin that helps prevent the main side effect from the busulfan that is a type of inflammation the mouth, stomach and bowels called mucositis. After this 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 necessary to 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 are rescued by 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 life-saving for an infant with XSCID, a subset of patients fail to achieve sufficient long lasting restoration of immunity to prevent infections and other chronic problems. Recent 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 T-lymphocyte leukemia and 1 died of this leukemia. Furthermore, when older children with XSCID were treated with gene transfer, the restoration of immunity was very 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 suggests that safer and more effective vectors were needed, and that there also may be a need to give chemotherapy 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- HgammaC-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 study purpose is to evaluate safety and effectiveness of lentiviral gene transfer treatment at restoring immune function to 13 XSCID patients who are 2 to 40 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 gammac gene and improved laboratory measures of immune function. The primary endpoint for efficacy will be at 2 years after treatment, and will include these laboratory parameters plus evidence for clinical benefit. Evidence for safety will focus on maintenance of a diversity of gene marked cells and no occurrence of abnormal pattern 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, and long term safety and efficacy evaluation will continue at intervals during the long term follow-up required by regulation in gene transfer treatment studies.


- INCLUSION CRITERIA: - A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA - HLA typing of the patient will have been performed before enrollment - No available HLA matched sibling donor as determined before enrollment. - Must be between 2 and 40 years of age and weigh greater than or equal to 10 kg - If previously transplanted, must be greater than or equal to 18 months post haploidentical HSCT - Expected survival of at least 120 days. - Documented to be negative for HIV infection by genome PCR - The patient must be judged by the primary evaluating physician to have a suitable family and social situation consistent with ability to comply with protocol procedures and the long-term follow-up requirements. - Medical lab data (historical) of severe B cell dysfunction (low or absent IgG levels, failed immune response to vaccines); OR demonstrated requirement for intravenous gamma globulin (IVIG) (significant drop over 3 to 6 weeks between peak and trough IgG levels). - Must be willing to have blood and tissue samples stored IN ADDITION, patients must satisfy the following Laboratory Criteria AND Clinical Criteria Laboratory Criteria: (greater than or equal to 1 must be present) i. CD4+ lymphocytes: absolute number less than or equal to 50 percent of the lower limit of normal (LLN) ii. CD4 plus CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs)squared less than or equal to 5 percent of normal for age. iii. Memory B Cells: absolute numberless than or equal to 50percent of LLN iv. If serum IgM<normal for age v. NK cells: absolute number less than or equal to 50 percent of LLN vi. Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), is squared 25 percent with a normal control. vii. Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks) in greater than or equal to 6 of the 24 V- Beta T-cell receptor families. Clinical Criteria: (greater than or equal to 1 must be present): i Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below): greater than or equal to 3 significant new or chronic active infections during the 12 months preceding evaluation for enrollment. Infections are defined as an objective sign of infection (fever greater than 38.3 degrees C [101 degrees F] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging evidence or typical lesion or histology or new severe diarrhea or cough with sputum production). In addition to one or more of these signs/symptoms of possible infection, there also must be at least 1 of the following criteria as evidence of the attending physician s intent to treat a significant infection (a. and b.) or objective evidence for a specific pathogen causing the infection (c.) -Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days OR -Hospitalization of any duration for infection OR -Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of infection ii Chronic pulmonary disease as defined by: -Bronchiectasis by x-ray computerized tomography OR -Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is less than or equal to 60 percent of Predicted for Age OR -Pulse oximetry less than or equal to 94 percent in room air (if patient is too young to comply with performance of PFTs). iii Gastrointestinal enteropathy: -Diarrhea-watery stools greater than or equal to 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion above) OR -Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated) OR -Other evidence of enteropathy or bacterial overgrowth syndrome: including malabsorption of fat soluble vitamin(s), abnormal D-xylose absorption, abnormal hydrogen breath test, evidence of protein losing enteropathy (for example increasingly high or frequent dosing of intravenous gamma globulin supplement required to maintain blood IgG level). iv Poor nutrition: Requires G-tube or intravenous feeding supplement to maintain weight or nutrition. v Auto- or allo-immunity: Examples must include objective physical findings that include, but are not limited to any one of alopecia, severe rashes, uveitis, joint pain with redness or swelling or limitation of movement that is not a result of infection, lupus-like lesions, and granulomas (Does not include auto- or allo-immune enteropathy which is criterion iii). Where possible and appropriate, diagnosis will be supported by histopathology or other diagnostic modality. vi Failure to grow in height: less than or equal to 3 rd percentile for age vii Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of greater than or equal to 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are greater than or equal to 3 warts at different anatomic sites at the same time; or the patient has both molluscum and warts) viii Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida intertriginous infection or candida nail infections; must be culture positive to satisfy this criterion) EXCLUSION CRITERIA: - Any current or pre-existing hematologic malignancy - Current treatment with any chemotherapeutic agent (becomes eligible if not on treatment for at least 3 months) - Documented HIV-1 infection - Documented active Hepatitis B infection - Childhood malignancy (occurring before 18 years of age) in the patient or a first degree relative, or previously diagnosed known genotype of the subject conferring a predisposition to cancer (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol)



Primary Contact:

Principal Investigator
Suk S De Ravin, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)

Nana Kwatemaa, R.N.
Phone: (301) 451-7820

Backup Contact:

Suk S De Ravin, M.D.
Phone: (301) 496-6772

Location Contact:

Bethesda, Maryland 20892
United States

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone: 800-411-1222

Site Status: Recruiting

Data Source:

Date Processed: August 31, 2019

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