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Protocol Details

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

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male
Min Age: 2 Years
Max Age: 40 Years

Referral Letter Required


Population Exclusion(s)



T cell, B cell, NK cell;
Gene Transfer;
Peripheral Blood Stem Cells;
Common Gamma Chain (gamma c);
Immune Reconstitution

Recruitment Keyword(s)



X-linked Severe Combined Immunodeficiency (XSCID)

Investigational Drug(s)

autologous CD34+ hematopoietic stem cells transduced with the lentivector, VSV-g

Investigational Device(s)



Biological/Vaccine: Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector
Drug: Busulfan
Drug: Palifermin

Supporting Site

National Institute of Allergy and Infectious Diseases

This is a non-randomized clinical trial using a lentiviral gene transfer vector (or lentivector, LV) to treat patients with X-linked severe combined immunodeficiency (XSCID) who have clinically significant impairment of immunity. We will collect the patient s own stem cells that will be transduced or exposed to the vector carrying a normal copy of the gene. The gene-corrected stem cells will be administered as a one-time infusion. Patients will receive a low-moderate dose of a chemotherapy drug called busulfan (6 mg/kilogram body weight) to allow engraftment of the stem cells. After the infusion, patients will be monitored to see if the treatment is safe and whether their immune system improves. Patients will be monitored for up to 15 years after treatment to assess immune function and the safety of the treatment.

XSCID is a genetic disease caused by defects in the common gamma chain, a protein found at the surface of immune cells called lymphocytes, and is necessary to their growth and function. XSCID patients cannot make T-lymphocytes necessary to fight infections, and their B-cells fail to make essential antibodies. Without normal T-and B-lymphocyte function, patients develop fatal infections in infancy unless they receive a bone marrow transplant from a healthy donor. The best type of transplant is from a tissue-matched healthy sibling, but most XSCID patients do not have a tissue-matched sibling and are treated with a transplant from a parent who is only half-matched by tissue typing. While a half-matched transplant from a parent can be lifesaving for an infant with XSCID, a subset of patients fail to achieve sufficient long-lasting restoration of immunity to prevent infections and other chronic problems.

Trials of gene transfer treatments using mouse retrovirus vectors for infants with XSCID have been performed and have shown this type of gene transfer can be an alternate approach for significantly restoring immunity to infants with XSCID. However, among the 18 infants with XSCID benefiting long-term from the gene transfer treatment, 5 developed T-lymphocyte leukemia and 1 died of this leukemia. When older children with XSCID were treated with gene transfer, the restoration of immunity was much less than seen in the infants. These observations of gene transfer treatments using mouse retrovirus vectors to treat infants and older patients with XSCID suggest that safer and more effective vectors were needed and that there also may be a need to give chemotherapy or another mode of conditioning to increase engraftment in the marrow of the gene-corrected blood stem cells. Our data and other published studies suggest that lentivectors derived from the human immunodeficiency virus and have the properties of our highly modified vector have a reduced interaction with nearby genes and therefore less of a tendency to activate genes that may lead to cancer formation. This type of lentivector may work better at getting into blood stem cells.

The study's purpose is to evaluate the safety and effectiveness of lentiviral gene transfer treatment in restoring immune function to 35 XSCID patients who are 2 to 40 years of age and have significant impairment of immunity. Early evidence for effectiveness will be defined by appearance and expansion in the circulation of the patient s gene-corrected T-lymphocytes with a functional >=c gene and improved laboratory measures of immune function. The primary endpoint for efficacy will be at 2 years after treatment and will include these laboratory parameters plus evidence for clinical benefit. Evidence for safety will focus on the maintenance of a diversity of gene-marked cells and no occurrence of abnormal patterns of production of blood cells or any leukemia or other cancer.

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-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 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 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 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. 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):

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.)

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


-Hospitalization of any duration for infection


-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


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


-Pulse oximetry 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)


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


-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 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


-Children: Children 2 years of age and older may enroll on this study because the condition under study affects children and the study holds the prospect for direct benefit.

-Adults who lack capacity to consent to research participation: Adults who are unable to consent are eligible for enrollment in this protocol because patients with SCID-X1 may have serious complications affecting decision-making ability and because the study intervention might provide direct benefit. Similarly, enrolled participants who lose the ability to provide ongoing consent (either

temporarily or permanently) during study participation may continue in the study following NIH Human Research Protection Program (HRPP) Policy 403, Research with Subjects Lacking Capacity to Consent. The risks and benefits of participation for adults unable to consent should be identical to those described for less vulnerable patients.

-Pregnant and Lactating Women: Pregnant women are excluded from this study because IL2RG gene is located on the X-chromosome and only males are affected. There are no female patients wtith X-linked SCID.


-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)

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Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL, Staal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK, Schmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008 Sep;118(9):3143-50. doi: 10.1172/JCI35798.

Kang EM, Choi U, Theobald N, Linton G, Long Priel DA, Kuhns D, Malech HL. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010 Jan 28;115(4):783-91. doi: 10.1182/blood-2009-05-222760. Epub 2009 Dec 1.

Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefr(SqrRoot)(Registered Trademark)re F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougn(SqrRoot)(Registered Trademark)res P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009 Nov 6;326(5954):818-23. doi: 10.1126/science.1171242.

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Principal Investigator

Referral Contact

For more information:

Suk S. De Ravin, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 10 - CRC BG RM 5-3816
(301) 496-6772

Suk S. De Ravin, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 10 - CRC BG RM 5-3816
(301) 496-6772

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


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