TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children

Overview

This research is being done to learn if a new type of haploidentical transplantation using TCR alpha beta and CD19 depleted stem cell graft from the donor is safe and effective to treat the patient's underlying condition. This study will use stem cells obtained via peripheral blood or bone marrow from parent or other half-matched family member donor. These will be processed through a special device called CliniMACS, which is considered investigational.

Eligibility

Inclusion Criteria:

1. Patient with any form of primary immune deficiency/dysregulatory disorders characterized by aberrant immune function, abnormal hematopoiesis, systemic or organ specific autoimmunity and/or non-malignant lymphoproliferation. This includes, but not limited to:
2. Disorders of phagocytes: Chronic granulomatous disease, Leukocyte adhesion deficiency, defects of IL-10 pathway, MonoMac syndrome

   II. Defects of cellular and humoral immunity: Severe Combined Immunodeficiency Disorder (infants with classic SCID up to 2 years of age will be excluded due to other open protocol), X-linked hyper-IgM syndrome, DOCK8 deficiency, ZAP70 deficiency, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, NEMO deficiency.

   III. Disorder of immune dysregulation: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, CTLA4 deficiency, LRBA deficiency, STAT1 GOF, STAT3 GOF, X-linked lymphoproliferative disease etc.

   IV. Other PIDs and immune dysregulatory disorders who can be benefitted by HCT as deemed appropriate by the PI and the treating immunologist.

3. Histiocytic disorders including hemophagocytic lymphohistiocytosis (familial HLH (types 1-5), secondary HLH (refractory to therapy or with recurrent episodes of hyper inflammation) and multisystem refractory Langerhans cell histiocytosis.
4. Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc.

Inclusion Criteria:

1. Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1.
2. Patients must have adequate organ function measured by:
   1. Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
   2. Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
   3. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2.
   4. Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age.
   5. Karnofsky or Lansky (age-dependent) performance score ≥ 50
3. Signed written informed consent

Exclusion Criteria:

1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded.
2. Pregnant or breastfeeding females.
3. Patient has HIV or uncontrolled fungal, bacterial or viral infections.
4. Patient has received prior solid organ transplant.
5. Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.