Experience with cultured thymus tissue in 105 children.
22q11.2
CHARGE syndrome
CTT
Congenital athymia
RVT-802
complete DiGeorge
thymus transplantation
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
26
02
2021
revised:
23
06
2021
accepted:
29
06
2021
pubmed:
8
8
2021
medline:
4
3
2022
entrez:
7
8
2021
Statut:
ppublish
Résumé
Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia. Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia. A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded. A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT. Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT.
Sections du résumé
BACKGROUND
Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia.
OBJECTIVE
Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia.
METHODS
A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded.
RESULTS
A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT.
CONCLUSION
Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT.
Identifiants
pubmed: 34362576
pii: S0091-6749(21)01056-3
doi: 10.1016/j.jaci.2021.06.028
pmc: PMC8810898
mid: NIHMS1743539
pii:
doi:
Substances chimiques
Forkhead Transcription Factors
0
Whn protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
747-757Subventions
Organisme : NIAID NIH HHS
ID : R01 AI047040
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI038550
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI054843
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI047040
Pays : United States
Organisme : FDA HHS
ID : R01 FD002606
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI060967
Pays : United States
Organisme : FDA HHS
ID : R01 FD003528
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Clin Immunol. 2010 May;135(2):236-46
pubmed: 20236866
Blood. 2011 Jan 13;117(2):688-96
pubmed: 20978268
Medicine (Baltimore). 2011 Jan;90(1):1-18
pubmed: 21200182
Am J Transplant. 2008 Aug;8(8):1729-36
pubmed: 18557726
Bioinformatics. 2005 Aug 15;21(16):3394-400
pubmed: 15955781
Clin Exp Immunol. 2013 Jul;173(1):140-9
pubmed: 23607606
Blood. 2010 Sep 30;116(13):2229-36
pubmed: 20530285
J Immunol. 2008 May 1;180(9):6354-64
pubmed: 18424759
J Pediatr Surg. 2004 Nov;39(11):1607-15
pubmed: 15547821
Blood. 2004 Oct 15;104(8):2574-81
pubmed: 15100156
PLoS Comput Biol. 2009 Jun;5(6):e1000396
pubmed: 19521511
Pediatrics. 2019 Feb;143(2):
pubmed: 30683812
Blood. 2007 May 15;109(10):4539-47
pubmed: 17284531
J Immunol. 1997 Jan 15;158(2):998-1005
pubmed: 8993022
N Engl J Med. 1999 Oct 14;341(16):1180-9
pubmed: 10523153
Blood. 2003 Aug 1;102(3):1121-30
pubmed: 12702512
Sci Immunol. 2020 Feb 28;5(44):
pubmed: 32111619