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

Study Overview
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Brief Summary
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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.

Official Title
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Study of TCR Alpha Beta T-Cell and CD19 B-Cell Depletion for Hematopoietic Cell Transplantation From Haploidentical Donors in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children

Conditions
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Primary Immune Deficiency Disorders, Metabolic Disease

Intervention / Treatment
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* Biological: Haploidentical Hematopoietic Cell Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: I. 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. 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. Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc. Inclusion Criteria: 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. Patients must have adequate organ function measured by: Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26% 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. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2. Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age. Karnofsky or Lansky (age-dependent) performance score ≥ 50 Signed written informed consent Exclusion Criteria: 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. Pregnant or breastfeeding females. Patient has HIV or uncontrolled fungal, bacterial or viral infections. Patient has received prior solid organ transplant. Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCR alpha beta T cell depletion<br>The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol | Biological: Haploidentical Hematopoietic Cell Transplantation<br>* TCR alpha beta T-cell and CD19 B-cell depleted haploidentical transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of successful donor engraftment | The incidence of engraftment at day 100 will be described based on donor chimerism in the whole blood and or fractions sorted for T-cell and myeloid subsets. The donor chimerism will be scored as autologous reconstitution (< 5% donor), mixed chimerism (5-49%=low mixed, 50-95%=high mixed), > 95%=full donor chimerism. | Day 100 after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival and Event-free survival | Overall survival is defined as the time of enrollment to death from any cause or last follow up. Event-free survival is defined as the time of enrollment to death, primary or secondary graft failure, graft failure necessitating a second HCT procedure, DLI or stem cell boost given for treatment of falling chimerism, or disease recurrence | Up to 2 years post transplant | 
| Kinetics of neutrophil engraftment | Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days | Up to 42 days post transplant | 
| Kinetics of platelet engraftment | Platelet engraftment defined as sustained platelet count >20,000/μL and >50,000//μL with no platelet transfusions in the preceding seven days. | Up to 42 days post transplant | 
| Transplant-related mortality | Rate of transplant-related mortality | Up to 100 days post transplant | 
| Acute grade II-IV GvHD | Incidence and severity of acute graft versus host disease | Up to 2 years post transplant | 
| Chronic GvHD | Incidence and severity of chronic graft versus host disease | Up to 2 years post transplant | 
| Primary graft failure | Rates of primary graft failure | Up to 2 years post transplant | 
| Secondary graft failure | Rates of secondary graft failure | Up to 2 years post transplant | 
| Transplant-related complications | Frequency of transplant-related complications following transplantation | Up to 2 years post transplant | 
| Transplant-related infections | Frequency of transplant-related infections following transplantation | Up to 2 years post transplant | 
| Cellular and Immunological reconstitution by laboratory evaluations | The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+) | Up to 2 years post transplant |