Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
X-linked Severe Combined Immunodeficiency (XSCID)
About this trial
This is an interventional treatment trial for X-linked Severe Combined Immunodeficiency (XSCID) focused on measuring T cell, B cell, NK cell, Gene Transfer, Peripheral Blood Stem Cells, Common Gamma Chain (gamma c), Immune Reconstitution
Eligibility Criteria
- INCLUSION CRITERIA:
- A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA
- HLA typing of the patient will have been performed before enrollment
- No available HLA matched sibling donor as determined before enrollment.
- Must be between 2 and 40 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 haploidentical HSCT
- Expected survival of at least 120 days.
- 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
- 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.
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 plus CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs)squared less than or equal to 5 percent of normal for age.
iii. Memory B Cells: absolute numberless than or equal to 50percent of LLN
iv. If 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 squared 25 percent 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 V- Beta 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): greater than or equal to 3 significant new or chronic active infections during the 12 months preceding evaluation for enrollment.
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.)
-Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days
OR
-Hospitalization of any duration for infection
OR
-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:
-Bronchiectasis by x-ray computerized tomography
OR
-Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is less than or equal to 60 percent of Predicted for Age
OR
-Pulse oximetry less than or equal to 94 percent in room air (if patient is too young to comply with performance of PFTs).
iii Gastrointestinal enteropathy:
-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
-Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated)
OR
-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 3 rd percentile for age
vii Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of greater than or equal to 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are greater than or equal to 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
- Current treatment with any chemotherapeutic agent (becomes eligible if not on treatment for at least 3 months)
- 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)
Sites / Locations
- National Institutes of Health Clinical Center
Arms of the Study
Arm 1
Arm 2
Other
Other
cohort a
cohort b
First 8 Patients Treated
Patients 9 and Beyond