haplocompatible transplant using tcrα/β depletion followed by cd45ra-depleted donor lymphocyte infusions for severe combined immunodeficiency (scid)

Conditions: Severe Combined Immunodeficiency

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.

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.

Eligibility 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

Keywords: severe combined immunodeficiency scid tcrα/β/cd19-depleted graft cd45ra-depleted dli graft-versus-host-disease transplant