Gene therapy for children with X-linked severe combined immunodeficiency

Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency

This study is testing a new gene therapy for children with X-linked severe combined immunodeficiency to see if it can safely help their immune system work better.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 2 Years to 50 Years
• Sex: Male
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: chemotherapy, radiation
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT01306019 on ClinicalTrials.gov

What this trial studies

This clinical trial is designed to evaluate the safety and efficacy of a lentiviral gene transfer treatment for children aged 2 to 50 years with X-linked severe combined immunodeficiency (XSCID). The approach involves collecting the patient's own hematopoietic stem cells, which are then genetically modified using a lentiviral vector to correct the underlying genetic defect. Following conditioning with busulfan, the modified stem cells are infused back into the patient to restore immune function. The study aims to monitor the engraftment and function of these gene-corrected cells over time.

Who should consider this trial

Good fit: Ideal candidates for this study are children aged 2 to 50 years with a confirmed mutation in the common gamma chain gene and no available HLA-matched sibling donor.

Not a fit: Patients who have a suitable HLA-matched sibling donor or those with other forms of immunodeficiency may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve immune function and quality of life for children suffering from XSCID.

How similar studies have performed: Previous studies using similar gene transfer techniques have shown promise in treating genetic immunodeficiencies, indicating potential for success in this approach.

Eligibility criteria

* INCLUSION CRITERIA:
* A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA
* No available HLA matched sibling donor as determined before enrollment. (HLA typing will be performed prior to enrollment)
* Must be between 2 and 50 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 HSCT
* Expected survival of at least 120 days.
* Participants of reproductive potential must agree to consistently use highly effective contraception throughout study participation and for at least 2 years post-treatment. Acceptable forms of contraception are:

  --For males: Condoms or other contraception with partner.
* 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+ CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs) less than or equal to 5 percent of normal for age.

III. Memory B Cells: absolute number less than or equal to 50 percent of LLN

IV. 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 \<= 25 percent compared 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 VBeta 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):

Three significant new or chronic active infections during the 2 years preceding evaluation for enrollment, with each infection accounting for one criteria.

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.)

1. Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days

   OR
2. Hospitalization of any duration for infection

   OR
3. 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:

1. Bronchiectasis by x-ray computerized tomography

   OR
2. Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is 60 percent of Predicted for Age

   OR
3. Pulse oximetry 94 percent in room air (if patient is too young to comply with performance of PFTs).

III. Gastrointestinal enteropathy:

1. 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
2. Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated)

   OR
3. 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 3rd percentile for age

VII. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are 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)

IX. Hypogammaglobulinemia: requires regular IgG supplementation

EXCLUSION CRITERIA:

* Any current or pre-existing hematologic malignancy
* 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)

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Suk S De Ravin, M.D. — National Institute of Allergy and Infectious Diseases (NIAID)
• Study coordinator: Suk S De Ravin, M.D.

Conditions X-linked Severe Combined Immunodeficiency; T cell, B cell, NK cell; Gene Transfer; Peripheral Blood Stem Cells; Common Gamma Chain; Immune Reconstitution