Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)

Launched by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) · Feb 26, 2011

Keywords

ClinConnect Summary

This clinical trial is studying a new treatment for boys aged 2 to 40 years who have a serious genetic condition called X-linked Severe Combined Immunodeficiency (XSCID). XSCID affects the immune system, making it hard for the body to fight infections, and is caused by a faulty gene. The trial uses a method called lentiviral gene transfer, where doctors will collect the patient's own blood stem cells, add a normal copy of the gene to them, and then give these corrected cells back to the patient through an infusion. To help these treated cells grow in the body, participants will receive a low dose of a chemotherapy drug before the infusion.

To be eligible for this trial, participants must have a confirmed mutation in the gene that causes XSCID and must not have an available sibling donor for a bone marrow transplant. They should also have certain signs of immune dysfunction, like low levels of immune cells or antibodies. After the treatment, participants will be closely monitored for safety and to see if their immune system improves over the next 15 years. This trial aims to find out if this new approach can safely restore immune function and help prevent serious infections in these children.

Gender

MALE

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)