Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
- Conditions
- X-linked Severe Combined Immunodeficiency (XSCID)
- Interventions
- Biological: Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector
- Registration Number
- NCT01306019
- Brief Summary
This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 35 patients with XSCID who are between 2 and 50 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of approximately 6 mg/kg/body weight (target busulfan Area Under Curve is 4500 min\*micromol/L/day) delivered as 3mg/kg body weight on day 1 and dose adjusted on day 2 (if busulfan AUC result is available) to achieve the target dose, to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34+HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the Food and Drug Administration (FDA) Guidance "Long Term Follow-Up After Administration of Human Gene Therapy Products" https://www.fda.gov/media/113768/download for patients
participating in gene transfer clinical trials.
XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure.
We propose to offer gene transfer treatment to XSCID patients\^3 \>= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol.
Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector.
Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres...
- Detailed Description
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 to be used in this study 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, 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 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 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 suggests 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-EF1 - h \>=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 \>=c 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 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, and long-term safety and efficacy evaluation will continue at intervals during the long-term follow-up period recommended by the United States FDA for patients participating in gene transfer treatment studies.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Male
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description cohort a Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector First 8 Patients Treated cohort b Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector Patients 9 and Beyond cohort a Busulfan First 8 Patients Treated cohort b Busulfan Patients 9 and Beyond cohort a Palifermin First 8 Patients Treated cohort b Palifermin Patients 9 and Beyond
- Primary Outcome Measures
Name Time Method Early evidence for efficacy will be defined by appearance and expansion in the circulation of autologous transduced T-lymphocytes with functional gmama-c and improved laboratory measures of immune function in the interim evaluation of these para... 1 year successful, partial successful or failure
- Secondary Outcome Measures
Name Time Method evidence for efficacy at 2 years after treatment will include these same laboratory parameters measured at the 2 year time point plus evidence for clinical benefit 2 years maintenance of polyclonality of vector marking, the lack of emergence of a dominant gene marked clone in any hematopoietic lineage, and no occurrence of either hematologic dysplasia or any leukemia or other cancer resulting from the gene transfer
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States