Phase I/II Thymus Transplantation With Immunosuppression #950

Overview

The study purpose is to determine if cultured thymus tissue implantation (CTTI) (previously described as transplantation) with tailored immunosuppression based on the recipient's pre-implantation T cell population is a safe and effective treatment for complete DiGeorge anomaly. This study will also evaluate whether cultured thymus tissue implantation and parathyroid transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly and hypoparathyroidism.

Full Title of Study: “Phase I/II Trial of Thymus Transplantation With Immunosuppression, #950″

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2011

Detailed Description

Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In infants with complete DiGeorge anomaly and no T cells, cultured thymus tissue implantation (CTTI) without immunosuppression resulted in diverse T cell development and good T cell function. Some infants with no thymus have some T cells that presumably developed extrathymically; these T cells can reject a thymus graft.

The purpose of this study is to tailor immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes tailored immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately.

Patients with complete DiGeorge often have hypoparathyroidism, a life threatening condition. Successful CTTI does not result in improvement of the hypoparathyroidism. The patients must go to the clinic for frequent calcium levels and to the hospital for calcium infusions. These infants are at risk for seizures from low calcium. This study had a parental parathyroid transplant arm for subjects with hypoparathyroidism who require calcium replacement.

Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen the subject received was dependent on the immune findings as stated in the clinical protocol.

Interventions

  • Biological: Cultured Thymus Tissue for Implantation (CTTI)
    • Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor’s birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject’s quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of implantation and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.
  • Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation
    • For subjects w/ hypoparathyroidism, the subject may receive CTTI and parathyroid transplant. For parathyroid transplant, parental parathyroid donors are screened. Parathyroid is harvested from the parent who shares the most Human Leukocyte Antigens (HLA) alleles with the thymus donor. Parathyroid gland is minced and placed in quadriceps muscle; there is no dose. Parathyroid donors are monitored as outpatients until recipients’ discharge. Recipients’ calcium and PTH levels are monitored indefinitely. Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor’s birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject’s quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of CTTI and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.
  • Procedure: Blood Draw
    • Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow testing of T cell identity in the Complete DiGeorge subjects. If blood is not obtainable then a buccal swab may be done.
  • Drug: Rabbit anti-thymocyte globulin
    • Three doses of 2 mg/kg IV (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
  • Drug: Cyclosporine
    • In addition to RATGAM, subjects with typical cDGA with PHA responses >50,000 cpm, or atypical cDGA with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. If subject cannot tolerate Csa, Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of range, dosing is modified appropriately. Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. The Csa dose is dependent on T cell numbers and the target Csa trough levels. Csa is weaned as per protocol.
  • Drug: Tacrolimus
    • If unable to tolerate cyclosporine, then tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.
  • Drug: Methylprednisolone or Prednisolone
    • Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells >4,000cumm. Steroids are weaned as per protocol.
  • Drug: Daclizumab
    • In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Daclizumab 1 mg/kg single dose IV may be given depending on T cell counts. Administration of Daclizumab depends on T cell numbers and T cell activation. A single dose may be given after the administration of rabbit anti-thymocyte globulin and before CTTI. If Daclizumab is not given before CTTI, and, depending on the T cell numbers and T cell activation, a single dose of Daclizumab may be given 3-5 days after CTTI.
  • Drug: Mycophenolate mofetil
    • In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Mycophenolate mofetil 15 mg/kg/dose every 8 hours IV or enterally may be given depending on T cell counts. Mycophenolate mofetil may be given if the T cell count remains elevated 5 days after CTTI. If MMF is given, the dose is 15 mg/kg IV. MMF may be stopped at 35 days after CTTI or continued for up to six months after CTTI.

Arms, Groups and Cohorts

  • Experimental: Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression
    • Patients with complete DiGeorge Anomaly (cDGA) undergo cultured thymus tissue implantation (previously described as transplantation) with tailored immunosuppression based on the subject’s pre-implantation T cell numbers and function.
  • Experimental: CTTI with Parathyroid Transplantation w/immunosuppression
    • Patients with complete DiGeorge Anomaly (cDGA) undergoes cultured thymus tissue thymus implantation (previously described as transplantation) with tailored immunosuppression based on the subject’s pre-implantation T cell numbers and function. If the patient has hypoparathyroidism, and is eligible, the patient may also receive a parathyroid transplant.

Clinical Trial Outcome Measures

Primary Measures

  • Survival at 1 Year Post-CTTI
    • Time Frame: 1 year post-CTTI
    • Survival at 1 year post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.

Secondary Measures

  • Survival at 2 Years Post-CTTI
    • Time Frame: 2 years post-CTTI
    • Survival at 2 years post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
  • Immune Reconstitution Efficacy – Total CD3 T Cells
    • Time Frame: 1 year post-CTTI
    • The development of total CD3 T cells at one year as measured using flow cytometry
  • Immune Reconstitution Efficacy – Total CD4 T Cells
    • Time Frame: 1 year post-CTTI
    • The development of total CD4 T cells at one year as measured using flow cytometry
  • Immune Reconstitution Efficacy – Total CD8 T Cells
    • Time Frame: 1 year post-CTTI
    • The development of total CD8 T cells at one year as measured using flow cytometry
  • Immune Reconstitution Efficacy – Naive CD4 T Cells
    • Time Frame: 1 year post-CTTI
    • The development of total naive CD4 T cells at one year as measured using flow cytometry
  • Immune Reconstitution Efficacy – Naive CD8 T Cells
    • Time Frame: 1 year post-CTTI
    • The development of total naive CD8 T cells at one year as measured using flow cytometry
  • Immune Reconstitution Efficacy – Response to Mitogens
    • Time Frame: 1 year post-CTTI
    • Measurement of the T cell proliferative response to the mitogen phytohemagglutin (PHA).
  • Thymus Allograft Biopsy
    • Time Frame: 2 to 3 months post-CTTI
    • Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.

Participating in This Clinical Trial

Thymus Transplantation Inclusion:

  • Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother w/diabetes (type I, type II, gestational).
  • <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+ (cluster of differentiation 45RA) (naïve phenotype), or <5% of CD3+ count being CD62L+ CD45RA+

Atypical DiGeorge:

  • Must have, or have had, a rash. If rash present, rash biopsy must show T cells in skin. If rash & adenopathy resolved, must have >50/cumm T cells & naive T cell must be <50/cumm or <5% of T cells.

Typical DiGeorge:

  • CD3+ CD45RA+ CD62L+ T cells <50/mm3 or <5% of total T cells

Parathyroid Transplantation Additional Inclusion:

  • 2 studies in recipient which PTH<5 pg/ml when ionized calcium <1.1 mmol/L. Can be done anytime pre-tx; 1 must be done while at Duke Hospital.
  • Parent(s) willing & eligible to be donors

Thymus Transplantation Exclusion:

  • Heart surgery <4 wks pre-tx
  • Heart surgery anticipated w/in 3 months after proposed tx
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA
  • HIV infection
  • Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx
  • CMV(>500 copies/ml blood by PCR on 2 tests)
  • Ventilator dependence

Parathyroid Donor Inclusion:

  • >18 years of age
  • Serum calcium in normal range
  • Normal PTH function
  • HLA typing consistent with parentage
  • Not on anticoagulation or can come off
  • Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the recipient. If no HLA matching at all, then either parent is acceptable if the parent meets other criteria.

Parathyroid Donor Exclusion:

  • <18 years old
  • Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate
  • Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low serum phosphate.
  • History of cancer
  • Donor only living involved parent/guardian of recipient
  • Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Chagas disease
  • Creutzfeldt Jakob disease (CJD)
  • Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit
  • Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD risk factors but not active disease, parent may give permission for parathyroid use.}
  • Urine CMV positive
  • Positive CMV IgM
  • Positive IgM anti-EBV VCA
  • On blood thinners and cannot stop for parathyroid donation
  • Elevated PT or PTT (>ULN)
  • Platelets<100,000
  • Positive Toxoplasma IgM
  • Donor will receive a history and physical; may be excluded based on PI's medical judgment.
  • Hemoglobin <9g/dl
  • Infectious head or neck lesion
  • Goiter on ultrasound
  • Abnormal fiberoptic laryngoscopy of vocal cords
  • HLA inconsistent with parentage
  • Pregnancy
  • Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is HSV IgG+.
  • Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+.
  • Medical concern of independent otolaryngologist.
  • Concern by medical psychologist/social worker that potential donor isn't competent or does not understand risks.
  • Questionnaire responses can lead to exclusion.

Mother of DiGeorge Inclusion:

• Provides consent to use blood/buccal sample. No exclusions except unwillingness to consent; or, provide blood/buccal sample.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • M. Louise Markert
  • Collaborator
    • National Institutes of Health (NIH)
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: M. Louise Markert, Professor of Pediatrics – Duke University
  • Overall Official(s)
    • M. Louise Markert, MD, PhD, Principal Investigator, Duke University Medical Center, Pediatrics, Allergy & Immunology

References

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. Epub 2007 Feb 6.

Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood. 2004 Oct 15;104(8):2574-81. Epub 2004 Apr 20.

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.

Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008 Apr;35(4):380-5. doi: 10.1111/j.1600-0560.2007.00816.x.

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. Epub 2007 Dec 26.

Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J Allergy Clin Immunol. 2004 Apr;113(4):734-41.

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. Epub 2003 Apr 17.

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.

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.

Citations Reporting on Results

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. Review.

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.

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. Epub 2007 Nov 26. Review.

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.

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.

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.

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.

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