Serum-Free Thymus Transplantation in DiGeorge Anomaly

Phase 1TerminatedNCT00849888

Sumitomo Pharma Switzerland GmbH2 enrolled

Overview

The study purpose is to determine if thymus tissue cultured in a serum-free (SF) solution is a safe and effective treatment for atypical and typical complete DiGeorge anomaly. \[Funding Source - FDA OOPD\]

Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, patients remain immunodeficient and usually die by age 2 years. In "typical" complete DiGeorge subjects who have no T cells, thymus transplantation without immunosuppression has resulted in diverse T cell development and good T cell function. In "atypical" complete DiGeorge subjects who have no thymus, a rash, and some T cells that presumably developed extrathymically, thymus transplantation with immunosuppression has resulted in diverse T cell development and good T cell function. Thus far, thymus transplantation studies have used thymus cultured in fetal bovine serum (FBS medium). This protocol's purpose is to determine whether transplanted thymus cultured in serum free medium can safely support thymopoiesis and T cell reconstitution as does FBS medium cultured thymus tissue in DiGeorge anomaly subjects. This protocol includes 2 arms: atypical DiGeorge subjects who will receive immunosuppression and thymus transplantation; and, typical complete DiGeorge subjects who will receive thymus transplantation without immunosuppression. Serum free medium use would reduce concerns of animal product exposure including potential exposure to bovine spongiform encephalopathy(BSE).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

DiGeorge Anomaly

Interventions

Serum Free Thymus Transplantation with ImmunosuppressionBIOLOGICAL

Cyclosporine pre-transplant (trough 180-220ng/ml) until naive T cells develop. Subjects \>4,000/cumm T cells, pre-transplant methylprednisolone or prednisolone 1-2mg/kg/day. All subjects pre-transplant days -5,-4,-3: 3 doses 2mg/kg rabbit anti-thymocyte globulin. Thymus tissue (unrelated donor), donor, \& donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects, FBS cultured thymus is transplanted in 1 leg \& serum free (SF) in other. After first 2 subjects \>10% naïve T cells, 3rd receives only SF thymus. After 3rd subject \>10%naive T cells, 4th subject transplanted. Thymus dose 4-18 grams/m2 body surface area. Thymus biopsy 8-12 weeks post-transplant. Skin biopsy at time of transplant \& thymus biopsy. Followed by immune evaluations.

Serum Free Thymus Transplantation without immunosuppressionOTHER

Thymus tissue (unrelated donor), donor, \& donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects: FBS cultured thymus transplanted in 1 leg \& serum free cultured thymus in other leg. After first 2 subjects have thymopoiesis in serum-free biopsy, \>10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject \>10% naive T cells, 4th subject receives transplant of only serum free cultured thymus. Dose 4-18grams/m2 body surface area. At time of transplant, skin biopsy. Allograft biopsy \& skin biopsy done 8 to 12 weeks post-transplant. (Graft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples, for two years.

Eligibility

Sex: ALLMax age: 2 Years

Medical Language ↔ Plain English

Thymus Recipients Inclusion: Complete DiGeorge anomaly diagnosis Must have one of following: * congenital heart disease * hypocalcemia requiring replacement * 22q11 or 10p13 hemizygous * CHARGE Atypical Arm: * Must have, or have had, rash. If rash present, skin biopsy must show T cells. If rash resolved, must have \>50/cumm T cells; \& \<50/cumm naive T cells or \<5% total * PHA response must be \<40000 counts per minute(cpm) on immunosuppression; or, \<75000cpm off immunosuppression. PHA test must be done 2x * CD45RA+CD62L+ CD3+ T cells must be \<50/mm3; or, \<5% of total CD3. Test must be done 2x Typical Arm: * PHA response \<20 fold or \<5,000cpm * Circulating CD3+CD45RA+CD62L+T cells \<50/mm3 or \<5% total T cells * 2 tests of T cells \& PHA response must show similar results Biological Mother Inclusion: -Must be recipient's biological mother Thymus Recipient Exclusion: * Heart surgery \<4 weeks pre-transplant or within 3 months post-transplant * Rejection by surgeon or anesthesiologist as surgical candidates * Lack of sufficient muscle tissue to accept transplant * Medical condition does not allow to undergo a biopsy * HIV * CMV(\>500 copies/ml blood by PCR on 2 tests) * Ventilator dependence * GVHD * Maternal T cells \>20% of total T cells * Prior immune reconstitution attempts (e.g., BMT, prior thymus transplant) * Hypoparathyroidism meeting criteria for combined thymus/parathyroid transplant \& parents desiring it * RSV or parainfluenza virus * Enterovirus or Adenovirus in stool Biological Mother Exclusion: -Unwillingness to sign consent or provide blood/buccal samples

Outcomes

Primary Outcomes

Survival

Survival at one year post thymus transplantation.

Time frame: One year post-thymus transplantation.

Incidence of graft-versus-host-disease (GVHD).

Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor.

Time frame: One year post-thymus-transplantation.

Thymopoiesis or graft rejection on biopsy.

Graft rejection analysis by biopsy at 2 months post-thymus transplantation.

Time frame: Two months post-thymus transplantation.

Secondary Outcomes

Incidence of autoimmune disease.

Incidence of autoimmune disease by year 2 after transplantation Cytopenias as assessed by complete blood counts and differential. Thyroid disease as assessed by thyroid function tests

Time frame: By two years post-thymus transplantation.

Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function.

Number of naïve CD4 T cells at one year after transplantation Number of total CD4 T cells at one year after transplantation Proliferative response to PHA at one year after transplantation TCRBV diversity by spectratyping measured by DKL score at one year after transplantation

Time frame: One year post-thymus transplantation.

Data from ClinicalTrials.gov

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