Thymus Transplantation in DiGeorge Syndrome #668

Sumitomo Pharma

Status and phase: Completed; Phase 2

Conditions: Complete Typical DiGeorge Anomaly; DiGeorge Syndrome

Treatments: Biological: Cultured Thymus Tissue for Implantation (CTTI)

Study type: Interventional

Funder types: Industry; NIH

Identifiers

NCT00576407

5K12HD043494-09 (U.S. NIH Grant/Contract)

#668 (Other Identifier)

Pro00009955

R56 Bridge R01AI4704011A1 (Other Grant/Funding Number)

R01AI054843 (U.S. NIH Grant/Contract)

3R56AI047040-11A1S1 (U.S. NIH Grant/Contract)

R01AI047040 (U.S. NIH Grant/Contract)

2R01AI047040-11A2 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The study purpose is to determine whether cultured thymus tissue implantation (CTTI) is effective in treating typical complete DiGeorge syndrome.

Full description

There is no safe and effective treatment for DiGeorge syndrome and most patients die by the age of two. Complete DiGeorge syndrome is characterized by very low T cell or very low naïve T cell numbers. In this study, typical complete DiGeorge syndrome subjects underwent human postnatal cultured thymus tissue implantation (CTTI). Thymus tissue that would otherwise be discarded was processed and then implanted into complete DiGeorge subjects in the operating room. At the time of CTTI, a skin biopsy may have been obtained to look for any preexisting T cells. After CTTI, subjects were followed by routine research immune evaluations, using blood samples obtained approximately every 2-4 weeks. At approximately 2-3 months post-CTTI subjects underwent an open biopsy of the allograft. The biopsy was done under general anesthesia in the operating room. At the time of the graft biopsy, another skin biopsy was obtained to look for clonal populations of T cells.

The protocol aims include: assessing thymopoiesis in the allograft biopsy; assessing immunoreconstitution of complete DiGeorge syndrome subjects after postnatal allogeneic cultured thymus tissue implantation; assessing minimally invasive methods of assessing thymopoiesis (flow cytometry and polymerase chain reaction (PCR); assessing pre-implant T cells which do not proliferate in response to mitogens (focusing on NK-T cells); and, assessing cultured thymus tissue implantation safety and toxicity.

Enrollment: 26 patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion criteria

• The subject's parent(s) signed the ICF.

• For a diagnosis of DiGeorge Syndrome (DGS), the subject had one of the following:

  • Heart defect
  • Hypoparathyroidism
  • 22q11 hemizygosity
  • 10p13 hemizygosity
  • Coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear anomalies/ deafness CHARGE association mutation (CHD7 deletion);
  • PHA proliferative responses less than 20-fold above background.

• Subjects with typical Complete DiGeorge Anomaly (cDGA) had to have one of the following on 2 separate occasions:

• Circulating CD3+ T cells by flow cytometry < 50/mm3 or PHA < 20-fold over background

  • If CD3+ were > 50/mm3, then CD45RA+ (cluster of differentiation 45RA) CD62L+ had to be < 50/mm3
  • Or T cell receptor rearrangement excision circles (TRECs) by PCR had to be < 100 per 100,000 CD3+ cells.

• Subjects with atypical cDGA had to have both of the following with 2 studies each:

  • Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.
  • T cell proliferative response to PHA more than 20-fold over background. Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.
  • T cell proliferative response to PHA more than 20-fold over background. While T cell response to PHA might have been seen, eligible subjects were to have no T cell proliferative response to antigens (less than 20-fold response) and were to have serious clinical problems related to immunodeficiency, such as opportunistic infection or failure to thrive.

Exclusion criteria

• Subjects on ventilators, with tracheostomies, with cytomegalovirus (CMV) infections, or requiring ongoing steroids could still be enrolled, but their data were to be analyzed separately
• Subjects who had heart surgery < 4 weeks prior to transplant
• Heart surgery anticipated within 3 months of the proposed time of transplantation
• Ongoing parenteral steroid therapy between enrollment and transplantation
• Present or past lymphadenopathy
• Rash associated with T cell infiltration of the dermis and epidermis
• Rejection by the surgeon or anesthesiologist as surgical candidates
• Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area (BSA) of the recipient
• Prior attempts at immune reconstitution, such as bone marrow transplantation or previous thymus transplantation
• Human immunodeficiency virus (HIV) infection

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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26 participants in 1 patient group

Cultured Thymus Tissue Implantation in Complete DiGeorge

Experimental group

Description:

Participants with Complete DiGeorge Syndrome, who were eligible, received cultured thymus tissue implantation (CTTI). No specific dose was assigned. There was a one time administration of the cultured thymus tissue.

Treatment:

Biological: Cultured Thymus Tissue for Implantation (CTTI)