Severe Combined Immunodeficiency, X-Linked
Conditions
Brief summary
Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. SCID arises from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor gamma chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL2RG). Allogeneic haematopoietic stem cell transplantation (HSCT), which replaces the patient's bone marrow with that of a healthy donor, is the only treatment that definitively restores the normal function of the bone marrow. HSCT is the first choice of treatment for patients with signs of bone marrow failure and a fully-matched related donor. However, patients without a fully-matched related donor have much worse overall outcomes from HSCT. This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy. To do this the investigators propose to perform a phase I/II clinical trial to evaluate the safety and efficacy (effect) of gene therapy for SCID-X1 patients using a lentivirus delivery system containing the IL2RG gene. Up to 5 eligible SCID-X1 patients will undergo mobilisation and harvest of their haematopoietic stem precursor cells (HPSCs). In the laboratory the disabled lentivirus will be used to insert a normal human IL2RG gene into the patient's harvested HPSCs. Patients will receive chemotherapy conditioning prior to cell infusion, in order to enhance grafting. The genetically corrected stem cells will then be re-infused into the patient. Patients will be followed up for 2 years. This trial will determine whether gene therapy for SCID-X1 using a lentiviral vector is safe, feasible and effective
Interventions
Gene therapy for X-linked Severe Combined Immunodeficiency will be performed by introduction a normal copy of the IL2RG gene into the blood forming stem cells (CD34+ cells) of the patient's bone marrow by using a type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient.
Sponsors
Great Ormond Street Hospital for Children NHS Foundation Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
8 Weeks to 5 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA \<10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG 2. Lack of an HLA identical (A, B, C, DR, DQ) related donor 3. Age \<5 years 4. Signed informed consent 5. Documentation of willingness to follow up for 15 years post-infusion 6. If the patient has previously undergone allogeneic transplant or gene therapy, insufficiency of graft-derived T cell engraftment must be documented. 7. Age at least 8 weeks of age by the time of busulfan administration
Exclusion criteria
1. Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below). 1. Mechanical ventilation including continuous positive airway pressure 2. Abnormal liver function defined by AST and ALT \>10 times the upper range of normal OR Bilirubin \>2 mg/dL 3. Shortening fraction on echocardiogram \<25% or ejection fraction \<50% 4. Renal failure defined as glomerular filtration rate \<30 ml/min/1.73 m2 or dialysis dependence 2. Uncontrolled seizure disorder 3. Encephalopathy 4. Documented coexistence of any disorder known to affect DNA repair 5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease 6. Patients with evidence of infection with HIV-1 7. Previous allogeneic transplant with cytoreductive chemotherapy 8. Major (life-threatening) congenital anomalies. Examples of major (life-threatening) congenital anomalies include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function. 9. Other conditions which in the opinion of the P.I. or Co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anaesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measure event-free survival after 1 year after gene transfer | 1 year | Event-free survival at 1 year post-infusion. Events will include death, infusion of unmanipulated back-up product for failure of haematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution |
| Measure T cell immune reconstitution; gene marking | 1 year | T cell reconstitution at 1 year post-infusion: Gene marking ≥0.1 copies/cell in sorted CD3+ T cells |
| Measure T cell immune reconstitution: CD3+ T cell count | 1 year | T cell reconstitution at 1 year post-infusion: CD3+ T cell count ≥300 cells/microliter in peripheral blood |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Calculate percentage of naïve and memory T cell subsets | up to 2 years post-infusion of gene therapy | Percentage of naïve and memory T cell subsets |
| Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution | up to 2 years post-infusion of gene therapy | Proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation |
| Measure antigen specific antibody titres to tetanus toxoid reconstitution | up to 2 years post-infusion of gene therapy | Measure antigen specific antibody titres to tetanus toxoid |
| Measure T cell receptor excision circles (TREC) | up to 2 years post-infusion of gene therapy | Measure T cell receptor excision circles (TREC) |
| Measure T cell receptor Vb family usage | up to 2 years post-infusion of gene therapy | Measure T cell receptor Vb family usage |
| To assess the efficacy of stem cell transduction/engraftment by measuring the frequency of gene marking in peripheral blood cells | up to 2 years post-infusion of gene therapy | Gene marking in specific lineages of peripheral blood cells. Genomic DNA isolated from each population will be assayed for VCN by quantitative PCR (qPCR). The results will be aggregated to determine the effectiveness of gene marking in the peripheral blood cells. |
| Measure clonal diversity of vector integrants | up to 2 years post-infusion of gene therapy | Clonal diversity will be quantitated and used to estimate the number of transduced haematopoietic stem cells that have engrafted in the subjects. Number of sequence reads and unique integration sites will be assessed to quantify population clone diversity, distribution of integration sites and relative abundance. |
| Measure overall survival | 2 years | Measure overall survival at 2 years post-infusion |
| Measure event-free survival | 2 years | Measure event-free survival at 2 years post-infusion |
| Incidence of adverse events related to gene therapy | up to 2 years post-infusion of gene therapy | Incidence of adverse events related to gene therapy |
| Enumeration of absolute lymphocyte count determined by routine complete reconstitution | up to 2 years post-infusion of gene therapy | Enumeration of absolute lymphocyte count determined by routine complete blood counts (CBC) |
| Haematopoietic recovery after receipt of busulfan | up to 6 weeks post-infusion of gene therapy | Haematopoietic recovery is defined as absolute neutrophil count above 0.5 x10\^9 /l for three consecutive days, achieved within 6 weeks following infusion. |
| Measure absolute numbers of T, B and NK lymphocytes | up to 2 years post-infusion of gene therapy | Absolute numbers of T, B and NK lymphocytes |
| Measure laboratory results which correlates with efficacious immune reconstitution | up to 2 years post-infusion of gene therapy | Percentage of naïve and memory B cell subsets |
| Determine Freedom from immunoglobulin substitution for at least 9 months | 2 years post-infusion of gene therapy | Freedom from immunoglobulin substitution for at least 9 months |
| Measure serum immunoglobulin levels reconstitution | up to 2 years post-infusion of gene therapy | Serum immunoglobulin levels |
Other
| Measure | Time frame | Description |
|---|---|---|
| Description of T cell receptor and B cell receptor repertoire before and after infusion | Pre-harvest, 3 month, 6 month, 12 month and 2 years post infusion of gene therapy | Description of T cell receptor and B cell receptor repertoire before and after infusion |
| Description of NK cell function and phenotype before and after infusion | Pre-harvest, 3 month, 6 month, 12 month and 2 years post infusion of gene therapy | Description of NK cell function and phenotype before and after infusion |
| Evidence of insertion site sharing between 2 or more lineages at 1 year and 2 years post infusion | 1 year and 2 years post infusion of gene therapy | Evidence of insertion site sharing between 2 or more lineages at 1 year and 2 years post infusion |
| Correlation of busulfan area-under-the-curve measurements prior to infusion with freedom from intravenous immunoglobulin substitution and antibody response to tetanus at 2 years post-infusion and other markers of humoral immune reconstitution | 2 years post-infusion of gene therapy | Correlation of busulfan area-under-the-curve measurements prior to infusion with freedom from intravenous immunoglobulin substitution and antibody response to tetanus at 2 years post-infusion and other markers of humoral immune reconstitution |
| Correlation of potential biomarkers of humoral immune reconstitution with freedom from intravenous immunoglobulin substitution and antibody response to tetanus at 2 years post infusion including: Gene marking in B cells and B cell phenotype. | at 6 month, 12 month and 2 years post-infusion of gene therapy | Correlation of potential biomarkers of humoral immune reconstitution at 6 months, 1 year, 2 years post infusion with freedom from intravenous immunoglobulin substitution and antibody response to tetanus at 2 years post infusion including: Gene marking in B cells and B cell phenotype. |
| Correlation of gene marking and insertion site sharing in expanded peripheral blood CD34+ cells with peripheral blood mature cell samples at 1 year and 2 years post infusion | 1 year and 2 years post infusion of gene therapy | Correlation of gene marking and insertion site sharing in expanded peripheral blood CD34+ cells with peripheral blood mature cell samples at 1 year and 2 years post infusion |
Countries
United Kingdom
Contacts
Primary ContactClaire Booth, Dr
Backup ContactKaren Oprych, Dr
Outcome results
None listed