This study is currently recruiting participants.
Number
11-I-0007
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: 50 Years
Referral Letter Required
Yes
Population Exclusion(s)
Female
Keywords
T cell, B cell, NK cell; Gene Transfer; Peripheral Blood Stem Cells; Common Gamma Chain (gamma c); Immune Reconstitution
Recruitment Keyword(s)
None
Condition(s)
X-linked Severe Combined Immunodeficiency (XSCID)
Investigational Drug(s)
autologous CD34+ hematopoietic stem cells transduced with the lentivector, VSV-g
Investigational Device(s)
Intervention(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
participating in gene transfer clinical trials.
XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure.
We propose to offer gene transfer treatment to XSCID patients^3 >= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol.
Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector.
Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres...
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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 numberless 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 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.) a.Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days OR b.Hospitalization of any duration for infection OR c.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: a.Bronchiectasis by x-ray computerized tomography OR b.Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is 60 percent of Predicted for Age OR c.Pulse oximetry 94 percent in room air (if patient is too young to comply with performance of PFTs). III. Gastrointestinal enteropathy: a.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 b.Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated) OR c.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 INCLUSION OF VULNERABLE PARTICIPANTS: -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. 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)
-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 numberless 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 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.)
a.Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days
OR
b.Hospitalization of any duration for infection
c.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:
a.Bronchiectasis by x-ray computerized tomography
b.Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is 60 percent of Predicted for Age
c.Pulse oximetry 94 percent in room air (if patient is too young to comply with performance of PFTs).
III. Gastrointestinal enteropathy:
a.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)
b.Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated)
c.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
INCLUSION OF VULNERABLE PARTICIPANTS:
-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.
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)
Principal Investigator
Referral Contact
For more information: