Clinical trial NCT03601286: Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency
Official title: Phase I/II Study of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Severe Combined Immunodeficiency, X-Linked
Lead sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
Sponsor class: OTHER
First posted: 2018-07-26
Enrollment: 5
Sex: MALE
Minimum age (years): 8
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Measure event-free survival after 1 year after gene transfer
timeFrame: 1 year
measure: Measure T cell immune reconstitution: CD3+ T cell count
timeFrame: 1 year
measure: Measure T cell immune reconstitution; gene marking
timeFrame: 1 year
Secondary outcomes:
measure: Measure overall survival
timeFrame: 2 years
measure: Measure event-free survival
timeFrame: 2 years
measure: Incidence of adverse events related to gene therapy
timeFrame: up to 2 years post-infusion of gene therapy
measure: Enumeration of absolute lymphocyte count determined by routine complete reconstitution
timeFrame: up to 2 years post-infusion of gene therapy
measure: Haematopoietic recovery after receipt of busulfan
timeFrame: up to 6 weeks post-infusion of gene therapy
measure: Measure absolute numbers of T, B and NK lymphocytes
timeFrame: up to 2 years post-infusion of gene therapy
measure: Calculate percentage of naïve and memory T cell subsets
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure laboratory results which correlates with efficacious immune reconstitution
timeFrame: up to 2 years post-infusion of gene therapy
measure: Determine Freedom from immunoglobulin substitution for at least 9 months
timeFrame: 2 years post-infusion of gene therapy
measure: Measure serum immunoglobulin levels reconstitution
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure antigen specific antibody titres to tetanus toxoid reconstitution
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure T cell receptor excision circles (TREC)
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure T cell receptor Vb family usage
timeFrame: up to 2 years post-infusion of gene therapy
measure: To assess the efficacy of stem cell transduction/engraftment by measuring the frequency of gene marking in peripheral blood cells
timeFrame: up to 2 years post-infusion of gene therapy
measure: Measure clonal diversity of vector integrants
timeFrame: up to 2 years post-infusion of gene therapy
Other outcomes:
measure: 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.
timeFrame: at 6 month, 12 month and 2 years post-infusion of gene therapy
measure: 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
timeFrame: 2 years post-infusion of gene therapy
measure: Evidence of insertion site sharing between 2 or more lineages at 1 year and 2 years post infusion
timeFrame: 1 year and 2 years post infusion of gene therapy
measure: 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
timeFrame: 1 year and 2 years post infusion of gene therapy
measure: Description of T cell receptor and B cell receptor repertoire before and after infusion
timeFrame: Pre-harvest, 3 month, 6 month, 12 month and 2 years post infusion of gene therapy
measure: Description of NK cell function and phenotype before and after infusion
timeFrame: Pre-harvest, 3 month, 6 month, 12 month and 2 years post infusion of gene therapy
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
state: Greater London
Study officials:
affiliation: UCL Great Ormond Street Institute of Child Health
name: Claire Booth, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: UCL Great Ormond Street Institute of Child Health
name: Adrian Thrasher, Prof
role: PRINCIPAL_INVESTIGATOR
References: