Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)

• Status: Recruiting
• Trial end date: 2028-07-01
• Target enrollment: 0
• Participant gender: All

Summary

Infants with severe combined immunodeficiency (SCID) have a profound decrease in number and function of immune cells, and therefore remain highly vulnerable to infection. If not corrected this often leads to death. Hematopoietic cell transplantation (HCT) from matched sibling donor is the standard treatment for these patients, unfortunately though; most SCID patients lack a sibling donor. Building upon experience and existing data, the investigators are proposing a trial the goals of which are: to provide a conditioning regimen that is well tolerated, and provision of immune cells that altogether should establish rapid immune recovery providing protection from life threatening infections without increasing the risk of dangerous Graft-Versus-Host-Disease.

Primary Objectives

1. To evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID

2. To estimate overall survival at 1 year post transplantation

Exploratory Objectives

1. To evaluate the significant donor T cell reconstitution of a TCRα/β/CD19 depleted graft with CD45RA-depleted DLI at 1 year (+/-2 weeks).

2. To evaluate engraftment at day 30, 100, month 6, and years 1 to 10 post HCT.

3. To evaluate B cell reconstitution at years 1 to 10 post HCT.

4. To evaluate biomarkers of immune reconstitution at day 30, 60 100, month 6 and years 1 to 10; e.g. immunophenotype (including epigenetic profiling) of T, B, and NK cells, and assays to determine their function.

5. To evaluate clinical outcomes, post HCT.

6. To define the incidence and severity of acute (at day 100, month 6), and chronic (month 6, 12, 24) GVHD following HCT.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: St. Jude Children's Research Hospital
• Treatments: Antilymphocyte Serum; Busulfan; Fludarabine; Fludarabine phosphate; Thiotepa; Thymoglobulin

Criteria

Inclusion Criteria - Transplant Recipient

• Age ≥2 months old at the time of chemotherapy administration

• A proven mutation as defined by direct sequencing of patient DNA

• Has a suitable matched sibling donor or matched unrelated donor (8/8) or single haplotype matched (≥3 of 6) family member donor

• Patient must fulfill pre-transplant evaluation:

• Left ventricular ejection fraction >40% and no evidence of uncorrected congenital malformation with clinical symptomatology

• Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2 or serum Creatinine ≤1.2mg/dL

• Resting pulse oximetry ≥90% on room or ≥95% on oxygen supplementation

• Lansky (age-dependent) performance score ≥50

• Bilirubin ≤3 times the upper limit of normal for age

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age

Exclusion Criteria - Transplant Recipient

• Positive for HIV infection by genome PCR

• Presence of active malignancy

• A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care

• Presence of a medical condition indicating that survival will be dismal such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy

Inclusion Criteria - Matched Sibling Donor and Haplocompatible Donor

• Fully matched sibling donor (8/8), or matched unrelated donor (8/8), or at least single haplotype matched (≥3 of 6) family member

• At least 1 year old (MSD) and at least 18 years of age (Haplocompatible)

• HIV negative

• Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female)

• Not breast feeding

• Regarding donation eligibility, is identified as either:

• Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR

• Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271