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

Overview

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

• Drug Lentiviral vector transduced CD34+ cells
  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.

Primary outcome measures

• Measure event-free survival after 1 year after gene transfer [Time frame: 1 year]
• Measure T cell immune reconstitution: CD3+ T cell count [Time frame: 1 year]
• Measure T cell immune reconstitution; gene marking [Time frame: 1 year]

Secondary outcome measures (12)

• Measure overall survival [Time frame: 2 years]
• Measure event-free survival [Time frame: 2 years]
• Incidence of adverse events related to gene therapy [Time frame: up to 2 years post-infusion of gene therapy]
• Enumeration of absolute lymphocyte count determined by routine complete reconstitution [Time frame: up to 2 years post-infusion of gene therapy]
• Haematopoietic recovery after receipt of busulfan [Time frame: up to 6 weeks post-infusion of gene therapy]
• Measure absolute numbers of T, B and NK lymphocytes [Time frame: up to 2 years post-infusion of gene therapy]
• Calculate percentage of naïve and memory T cell subsets [Time frame: up to 2 years post-infusion of gene therapy]
• Measure laboratory results which correlates with efficacious immune reconstitution [Time frame: up to 2 years post-infusion of gene therapy]
• Determine Freedom from immunoglobulin substitution for at least 9 months [Time frame: 2 years post-infusion of gene therapy]
• Measure serum immunoglobulin levels reconstitution [Time frame: up to 2 years post-infusion of gene therapy]
• Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution [Time frame: up to 2 years post-infusion of gene therapy]
• Measure antigen specific antibody titres to tetanus toxoid reconstitution [Time frame: up to 2 years post-infusion of gene therapy]

Eligibility criteria

Inclusion criteria

• 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
• Lack of an HLA identical (A, B, C, DR, DQ) related donor
• Age <5 years
• Signed informed consent
• Documentation of willingness to follow up for 15 years post-infusion
• If the patient has previously undergone allogeneic transplant or gene therapy, insufficiency of graft-derived T cell engraftment must be documented.
• Age at least 8 weeks of age by the time of busulfan administration

Exclusion criteria

• 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).

• Mechanical ventilation including continuous positive airway pressure
• Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL
• Shortening fraction on echocardiogram <25% or ejection fraction <50%
• Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence
• Uncontrolled seizure disorder
• Encephalopathy
• Documented coexistence of any disorder known to affect DNA repair
• Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
• Patients with evidence of infection with HIV-1
• Previous allogeneic transplant with cytoreductive chemotherapy
• 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 1 center

• Great Ormond Street Hospital for Children NHS Foundation Trust — London

Identifiers

NCT: NCT03601286 · 16IC17

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗