Experience with cultured thymus tissue in 105 children - 03/02/22
, Stephanie E. Gupton, CPNP a, Elizabeth A. McCarthy, RN, MSN aAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Congenital athymia, complete DiGeorge, CHARGE syndrome, 22q11.2, thymus transplantation, RVT-802, CTT
Abbreviations used : 22q11.2ds, AE, cDGA, CHARGE, Con A, CTT, CMV, EAS, FAS, GVHD, HSCT, PIV3, RATGAM, SCID, Treg
Plan
| M.L.M.’s writing efforts were supported by the Division of Pediatric Allergy, Immunology, and Pulmonary Medicine at Duke University. Funding of the writing efforts of S.E.G. and E.A.McC. was provided by the Thymus Research Fund. Statistical analyses were performed by Covance, Princeton, NJ, under contract with Enzyvant, for submission to the US Food and Drug Administration. Enzyvant has permitted these data to be used without charge. |
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| Funding for the research in this article includes the following: grant M01-RR30 (from The National Center for Research Resources, Clinical Research); grants U19-AI38550, U01-AI38587, R01-CA28936, U01-AI38587, R01-CA28936, R01-CA61227, R21-AG16826, and R21-AI44758; the American Association of Allergy, Asthma, and Immunology Women Physicians in Allergy Award; funding from Centeon Pharmaceutics and the Max Kade Foundation; grants R01-AI54843, R21-AI60967, FD-R-002606, and R01-AI47040; funding from the American Academy of Allergy Asthma and Immunology (Third-year FIT Research Award, 2006); grants R01-FD003528, 2R56-AI47040-11A1 (competitive revision), and 3R56-AI47040-11A1S1 (competitive revision supplement); and funding from the Hartwell Foundation. |
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| Disclosure of potential conflict of interest: Funding for this research was provided by Orphavant Sciences GmbH (later Enzyvant Therapeutics GmbH, ETG, Switzerland). Cultured thymus tissue (CTT) is an investigational product that is implanted into patients under an investigational new drug application with the US Food and Drug Administration. M. L. Markert is the “sponsor” of the investigations, and she developed the technology for CTT. Duke University has licensed the technology to Enzyvant Therapeutics GmbH, and M. L. Markert and Duke University have received royalties from Enzyvant. Portions of the salaries of M. L. Markert and her research team are being paid with funding from Enzyvant. If the technology is commercially successful in the future, M. L. Markert and Duke University may benefit financially. The salary and other items needed to create CTT are paid at cost by insurance. Enzyvant Therapeutics, Inc, reviewed this article for scientific accuracy and to ensure protection of their intellectual property. Editorial assistance, funded by Enzyvant Therapeutics, Inc, was provided by Lisa M Pitchford, PhD, of JB Ashtin. |
Vol 149 - N° 2
P. 747-757 - février 2022 Retour au numéro
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