Clinical trial NCT00576407: Thymus Transplantation in DiGeorge Syndrome #668
Official title: Phase II Study of Thymus Transplantation in Complete DiGeorge Syndrome #668
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: DiGeorge Syndrome
Complete Typical DiGeorge Anomaly
Keywords: Thymus Transplantation
DiGeorge Syndrome
Athymia
Low T cell numbers
Immunoreconstitution
Primary immunodeficiency
DiGeorge Anomaly
Complete DiGeorge
Typical DiGeorge
Cultured Thymus Tissue Implantation (CTTI)
Lead sponsor: Sumitomo Pharma Switzerland GmbH
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2007-12-19
Enrollment: 26
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI)
timeFrame: 1 year post-CTTI
Secondary outcomes:
measure: Survival at 2 Years Post-CTTI
timeFrame: 2 years post-CTTI
measure: Immune Reconstitution Efficacy - Total CD3 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Total CD4 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Total CD8 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Naive CD4 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Naive CD8 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Response to Mitogens
timeFrame: 1 year post-CTTI
measure: Thymus Allograft Biopsy
timeFrame: 2 to 3 months post-CTTI
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University Medical Center, Pediatrics, Allergy & Immunology
name: M. Louise Markert, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011 Sep;140(3):244-59. doi: 10.1016/j.clim.2011.04.004. Epub 2011 Apr 16.
citation: Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15.
citation: Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088.
citation: Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. doi: 10.1182/blood-2002-08-2545. Epub 2003 Apr 17.
citation: Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. doi: 10.1182/blood-2006-10-048652. Epub 2007 Feb 6.
citation: Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. doi: 10.1016/j.clim.2010.02.007. Epub 2010 Mar 16.
citation: Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.
citation: Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. doi: 10.1016/j.clim.2007.11.009. Epub 2007 Dec 26.
citation: Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64. doi: 10.4049/jimmunol.180.9.6354.
citation: Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. doi: 10.1016/j.smim.2007.10.002. Epub 2007 Nov 26.
citation: Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. doi: 10.1111/j.1600-6143.2008.02301.x. Epub 2008 Jun 28.
citation: Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5.
citation: Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, Victorino RM, Picard C, Debre M, Mahlaoui N, Fischer A, Sousa AE. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood. 2011 Jan 13;117(2):688-96. doi: 10.1182/blood-2010-06-292490. Epub 2010 Oct 26.
citation: Markert ML, Devlin BH, McCarthy EA, Chinn IK, Hale LP. Thymus Transplantation in Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. Eds Lavinin C, Moran CA, Morandi U, Schoenhuber R. Springer-Verlag Italia, Milan, 2008, pp 255-267.