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

Phase 2

Recruiting

• Conditions: Primary Immune Deficiency Disorders; Metabolic Disease
• Interventions: Biological: Haploidentical Hematopoietic Cell Transplantation

• Registration Number: NCT04414046
• Lead Sponsor: Johns Hopkins All Children's Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-05-24
• Study First Submitted QC: 2020-05-29
• Study First Posted: 2020-06-04
• Study Start: 2020-07-22
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-14
• Last Update Posted: 2024-06-17
• Primary Completion: 2025-06-30
• Study Completion: 2025-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 17

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:

   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.

2. 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.

3. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TCR alpha beta T cell depletion	Haploidentical Hematopoietic Cell Transplantation	The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol

Primary Outcome Measures

Name	Time	Method
Incidence of successful donor engraftment	Day 100 after transplantation	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.

Secondary Outcome Measures

Name	Time	Method
Overall survival and Event-free survival	Up to 2 years post transplant	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
Acute grade II-IV GvHD	Up to 2 years post transplant	Incidence and severity of acute graft versus host disease
Chronic GvHD	Up to 2 years post transplant	Incidence and severity of chronic graft versus host disease
Kinetics of platelet engraftment	Up to 42 days post transplant	Platelet engraftment defined as sustained platelet count \>20,000/μL and \>50,000//μL with no platelet transfusions in the preceding seven days.
Primary graft failure	Up to 2 years post transplant	Rates of primary graft failure
Transplant-related complications	Up to 2 years post transplant	Frequency of transplant-related complications following transplantation
Transplant-related mortality	Up to 100 days post transplant	Rate of transplant-related mortality
Cellular and Immunological reconstitution by laboratory evaluations	Up to 2 years post transplant	The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+)
Kinetics of neutrophil engraftment	Up to 42 days post transplant	Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days
Secondary graft failure	Up to 2 years post transplant	Rates of secondary graft failure
Transplant-related infections	Up to 2 years post transplant	Frequency of transplant-related infections following transplantation

Trial Locations

Locations (1)

Johns Hopkins All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States