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

In this study, the investigators propose to investigate T and B cell recovery using
peripheral blood manipulation that removes potentially Graft-Versus-Host-Disease (GVHD)
inducing α/β and CD45RA+ T cells, while still providing potentially beneficial donor γδ and
memory T cells.

Donors will undergo a standard hematopoietic progenitor cell (HPC) mobilization regimen
consisting of 5 days of G-CSF given subcutaneously at 10 micrograms/kilogram. The graft will
be collected by leukapheresis on days 5 and if needed 6 of G-CSF. The HPC product(s) will be
T-cell depleted (TCD) using the investigational CliniMACS device.

The initial HPC product(s) will be split into two portions; one portion will be used for TCR
TCRαβ/CD19 depletion and the second portion for CD45depleted DLI product.

1. TCRα/β/CD19-depleted stem cell transplant: All participants will undergo a preparative
regimen based on the type of Severe Combined Immunodeficiency (SCID) they have. This is
followed by infusion of TCRα/β/CD19-depleted donor cells (with the exception of
participants who undergo matched sibling donor HCT).

2. Donor Lymphocyte Infusion (CD45depleted DLI product): Participants, other than those who
undergo matched sibling HCT transplant, will receive one dose of CD45RA depleted DLI
infusion post TCRα/β/CD19-depleted graft infusion.

During the Phase I portion of the study, up to 4 different dose levels of CD45depleted DLI
product will be evaluated.

On the Phase II portion of the study, all participants will receive the Phase I determined
maximum tolerated dose (MTD) of DLI.

Participants on both the Phase I and Phase II portions of the study that are unable to
receive protocol defined dosing of DLI due to insufficient dose generated will be eligible to
receive the entirety of the generated product.

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