Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
Condition: Severe Combined Immunodeficiency
MeSH terms: Severe Combined Immunodeficiency; X-Linked Combined Immunodeficiency Diseases; Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Gene-Transduced Autologous CD34+ Stem Cells
Intervention type(s): Drug
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cells; Common Gamma Chain (GC); Immune Reconstitution; T Lymphocytes; B Lymphocytes; X-Linked Severe Combined Immune Deficiency (XSCID); Gene Therapy; NK Cell; Bone Marrow Transplantation; Engraftment; XSCID; Immune Deficiency; Immune System