Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)

Related Clinical Trial
cliniMACs HUD for T Cell Depletion Cord Blood Stem Cell Transplantation Study (COBLT) Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products Lentiviral Gene Therapy for Adenosine Deaminase (ADA) Deficiency Genetic Basis of Immunodeficiency IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency Sirolimus Prophylaxis for aGVHD in TME SCID Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant EZN-2279 in Patients With ADA-SCID AMG191 Conditioning/CD34+CD90 Stem Cell Transplant Study for SCID Patients Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1) Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID) Patients Treated for SCID (1968-Present) Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China Gene Therapy for ADA-SCID MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim Natural History Study of SCID Disorders Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency SCID Bu/Flu/ATG Study With T Cell Depletion Generalized Neonatal Screening of Severe Combined Immunodeficiencies Neonatal Screening of Severe Combined Immunodeficiencies Gene Therapy for X-linked Severe Combined Immunodeficiency An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID) Registry Study of Revcovi Treatment in Patients With ADA-SCID Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID

Brief Title

Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)

Official Title

Ex Vivo Retroviral Gene Transfer For Treatment of X-Linked Severe Combined Immunodeficiency (XSCID)

Brief Summary

      This is a clinical trial of gene therapy for X-linked severe combined immunodeficiency
      (XSCID), a genetic disease caused by defects in a protein called the common gamma chain,
      which is normally on the surface of immune cells called lymphocytes. XSCID patients cannot
      make T lymphocytes, and their B lymphocytes fail to make essential antibodies for fighting
      infections. Without T and B lymphocytes patients develop fatal infections in infancy unless
      they are rescued by a bone marrow transplant from a healthy donor. However, even transplanted
      patients may achieve only partial immune recovery and still suffer from many infections,
      auto-immunity and/or and poor growth. A recent, successful trial in France used gene therapy
      instead of bone marrow transplantation for infants with XSCID. This experience indicates that
      gene therapy can provide clinical benefit to XSCID patients. We will enroll eight older XSCID
      patients (1.5-20 years-old), who have previously received at least one bone marrow
      transplant, but still have poor T and B lymphocyte function that compromises their quality of
      life. Before enrollment, these subjects will have had some of their own blood-forming stem
      cells harvested and frozen in a blood bank. These cells have a defective gene, but a correct
      copy of the gene will be inserted while the cells are grown in sterile conditions outside the
      patient's body. To do this, the cells will be unfrozen and exposed for four days in a row to
      growth factors and particles of a retrovirus we have constructed and tested called "GALV
      MFGS-gc." Retrovirus particles will attach to the patient cells and introduce a correct copy
      of the common gamma chain gene into cells capable of growing into all types of blood cells,
      including T and B lymphocytes. XSCID patients who are enrolled in the study will receive a
      single dose of their own cells that have been modified by the GALV MFGS-gc treatment and also
      will be given another drug called palifermin to help prevent side effects from the
      chemotherapy and possibly try to improve the development of the T cells. After this, the
      patients will be monitored to find out if the treatment is safe and to see if their immune
      function improves. Study endpoints are (1) efficient and safe clinical-scale transduction of
      HSC from post-BMT XSCID subjects; (2) administration of a nonmyeloablative conditioning
      regimen in older patients to improve engraftment; (3) administration of a transduced HSC to
      eight subjects; (4) administration of KGF to improve thymic function post transplant to
      improve T cell development; and (5) appropriate follow-up of the treated subjects to monitor
      vector sequence distribution, gc expression in hematopoietic lineages, and lymphoctye numbers
      and function as well as general health and immune status.
    

Detailed Description

      This is a Phase I/II clinical trial of ex vivo hematopoietic stem cell (HSC) gene therapy for
      X-linked severe combined immunodeficiency (XSCID). XSCID results from defects in the IL2RG
      gene encoding the common gamma chain (gc) shared by receptors for Interleukin 2 (IL-2), IL-4,
      IL-7, IL-9, IL-15 and IL-21. XSCID patients generally lack T-lymphocytes and NK cells, and
      their B-lymphocytes fail to make essential antibodies. XSCID is fatal in infancy without
      immune reconstitution, such as by allogeneic bone marrow transplantation (BMT). However, many
      transplanted patients achieve only partial immune reconstitution, and consequently have
      recurrent infections, autoimmunity and/or poor growth. Recent successful retroviral gene
      therapy instead of BMT for infants with XSCID indicates that ex vivo gene therapy can provide
      clinical benefit to XSCID patients.

      We will enroll eight older XSCID patients (1.5-20 years-old; greater than or equal to 12 kg
      body weight), who have had attempted BMT, but who have persistent T-lymphocyte and
      B-lymphocyte impairments that compromise their quality of life. Prior to enrollment, these
      subjects will have had autologous CD34+ HSC mobilized by treatment with granulocyte colony
      stimulating factor (G-CSF), collected from peripheral blood by apheresis, immune selected and
      cryopreserved in sufficient numbers to achieve entry criteria (greater than or equal to 1.0 x
      10(6) CD34+ HSC/kg body weight). HSC procurement will be conducted under a separate, approved
      and active NIH protocol, 94-I-0073, 'Recruitment of peripheral blood hematopoietic
      progenitors by granulocyte colony stimulating factor [G-CSF]'.

      Autologous CD34+ HSC will be transduced ex vivo with the gibbon ape leukemia virus (GALV)
      envelope-pseudotyped, replication-defective, murine onco-retrovirus vector, MFGS-gc that
      encodes the common gamma chain. Transductions will occur in flexible gas-permeable plastic
      containers using serum-free medium supplemented with 1% human serum albumin and five
      recombinant growth factors (50 ng/mL Flt3-L, 50 ng/mL SCF, 50 ng/mL TPO, 25 ng/mL IL-6, and 5
      ng/mL IL-3). Subjects who are older than the age of 3 will be given a conditioning regimen
      consisting of Fludarabine and Busulfan then they will receive a single infusion of transduced
      HSC. Prior to the chemotherapy, and following the infusion of the cells, the same patients
      will also be given Keratinocyte growth factor (KGF), also known as palifermin. Subjects will
      be monitored for safety and efficacy; the latter evidenced by new development of autologous
      transduced lymphocytes with functional gc. Study endpoints are (1) efficient and safe
      clinical-scale transduction of HSC from post-BMT XSCID subjects; (2) administration of a
      nonmyeloablative conditioning regimen to improve engraftment; (3) administration of
      transduced HSC to eight subjects; (4) administration of KGF to improve thymic function post
      transplant to improve T cell development; and (5) appropriate follow up of treated subjects
      to monitor vector sequence distribution, gc expression in hematopoietic lineages, and
      lymphocyte numbers and function; as well as general health and immune status.
    

Study Phase

Phase 1

Study Type

Interventional




Condition

Severe Combined Immunodeficiency

Intervention

Gene-Transduced Autologous CD34+ Stem Cells


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

3

Start Date

December 10, 2001

Completion Date

July 25, 2011

Primary Completion Date

July 25, 2011

Eligibility Criteria

        -  INCLUSION CRITERIA:

        Patients must have XSCID as defined by either a deleterious mutation in IL2RG, the absence
        of or less than 5% of normal detectable gc protein, or evidence of functionally defective
        gc protein.

        Patients must be between 1.5 and 20 years of age.

        Patients must weigh at least 12 kg.

        Patients will have evidence of combined B-cell and T-cell immune deficiency over at least a
        6 month period despite previous allogeneic BMT at least 12 months prior to study entry.
        T-cell immune deficiency is defined as one or more of the following: Total T-cell count
        less than 500/ul; less than 50% of normal value for in vitro mitogen stimulation; or absent
        proliferation in vitro to antigens. B-cell immune deficiency is defined as one or more of
        the following: IgM, IgA or IgE values which are 2 or more standard deviations below the
        established value for normal, IgG values falling to less than 30% of normal during
        unintended interruptions or delay in the periodic administration of IVIG; or documented
        failure to respond to a specific antigen challenge.

        Patients must have less than or equal to 3% of their mobilized CD34+ cells deriving from
        their allogeneic bone marrow donor.

        Willingness to remain hospitalized for several days to several weeks.

        Have a primary care physician at home.

        Consent to permit blood and/or tissue samples for storage.

        EXCLUSION CRITERIA:

        Any current or preexisting hematologic malignancy.

        Current treatment with any chemotherapeutic agent.

        Current treatment with any immunosuppressive agent, excluding corticosteroids.

        Documented HIV-1 infection.

        Documented Hepatitis B infection.

        Childhood malignancy (occurring before 18 years of age) in the patient or a first degree
        relative, or known genotype of the subject conferring a predisposition to cancer.
      

Gender

All

Ages

18 Months - 20 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00028236

Organization ID

020057

Secondary IDs

02-I-0057


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

, , 


Verification Date

July 25, 2011