Experience with cultured thymus tissue in 105 children

Abstract

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.

Keywords: 22q11.2; CHARGE syndrome; CTT; Congenital athymia; RVT-802; complete DiGeorge; thymus transplantation.

FIG 1.

Flow chart of patient disposition at the end of year 2. *“Other” includes 2 patients with SCID, 6 patients with previous hematopoietic or fetal thymic transplants, and 2 patients in which diagnosis was not definitive. CTT, cultured thymus tissue; SCID, severe combined immunodeficiency.

FIG 2.

Kaplan Meier survival curve of EAS. This analysis shows that of the 95 patients, almost all deaths occurred in the first year. EAS, efficacy analysis set.

FIG 3.

Flow cytometry. A, Median numbers of lymphocytes in patients with typical phenotype. B, Median numbers of lymphocytes in patients with atypical phenotype. C, T cell subsets in patients with typical phenotype. D, T cell subsets in patients with atypical phenotype. E, Naïve T cells in patients with typical phenotype. Note, there were no patient samples for month 21. F, naïve T cells in patients with atypical phenotype. Normal values for age and interquartile data are in Table E5,A and Table E5,B in this article’s Online Repository at www.jacionline.org. ALC, absolute lymphocyte count; CTT, cultured thymus tissue; db neg, double negative; NK, natural killer.

FIG 4.

T cell proliferative responses to mitogens and antigens. Responses to A, PHA; B, Con A; and C, tetanus toxoid. The normal response to PHA is 85,000 to 286,636 cpm, to Con A is 75,000 to 224,079 cpm, and to tetanus toxoid is 11,273 to 106,085 cpm. Con A, concanavalin A; cpm, counts per minute; PHA, phytohemagglutinin.