Clinical trial NCT02274662: Expanded Access Protocol Thymus Transplantation
Official title: Expanded Access Protocol Thymus Transplantation for Immunodeficiency, Hematologic Malignancies, and Autoimmune Disease Related to Poor Thymic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Poor Thymic Function
Immunodeficiency
Athymia
Immunoreconstitution
Thymus Transplantation
Low T Cell Numbers
Keywords: Cultured Thymus Tissue Implantation
Lead sponsor: Sumitomo Pharma Switzerland GmbH
Sponsor class: INDUSTRY
First posted: 2014-10-24
Enrollment: 11
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose is to provide access for patients who have immunodeficiency or severe autoimmune disease related to poor thymic function to cultured thymus tissue for implantation. With no thymus function, bone marrow stem cells do not develop into educated T cells, which fight infection.

Eligible participants receive cultured thymus tissue for implantation and may undergo biopsy. Immune suppression may be given depending on the immune status and clinical condition of the participant. Immune function testing is continued for one year post-implantation.

Detailed description: The patients enrolled have a high likelihood of death if they do not receive culture thymus tissue because of lack of thymus function. As there are many types of patients who may be enrolled, study results will not have statistical significance.

The study objective is to make cultured thymus tissue available for implantation on an expanded access basis. Data will be collected on survival, naïve T cell development, T cell chimerism, and implant related toxicities, as well as any unexpected study-related serious adverse events.

Eligible subjects receive cultured thymus tissue and may undergo allograft biopsy. Immune suppression may be given depending on the subject's immune status and clinical condition.

Protocol specified studies continue until approximately one year post-implantation. Study participation lasts approximately two years.

Eligibility criteria: Cultured Thymus Tissue Inclusion Criteria for Implantation:

* an immunodeficiency or severe autoimmunity for which development of naïve T cells would be expected to lead to lead to clinical improvement.
* written consent (or consent of parent/legal guardian as applicable), review of medical testing, laboratory studies, and physical examinations are used to determine whether the patient is clinically stable and will potentially benefit from receiving cultured thymus tissue. Each participant is reviewed with the Data Safety and Monitoring Board (DSMB).

Cultured Thymus Tissue Exclusion Criteria for Implantation:

* Unrepaired cyanotic congenital heart disease
* Uncontrolled infections. "Uncontrolled" is defined as requiring a ventilator, dialysis, or vasopressor support or anticipated as requiring such support within 6 months.
* Pregnancy

  * For females of child-bearing potential, a serum pregnancy test is done after consent, at the same time another blood draw is done if possible.
  * Females of child-bearing potential must agree to contraceptive measures as indicated in the consent form.
  * A second serum pregnancy test is done within 48 hours prior to administration of study interventions involving FDA pregnancy class D drugs, chemotherapy drugs, or other drugs or interventions known to pose risks to a potential fetus.
* HIV Positive
* History of malignancy
* CMV Infection

  * For subjects receiving immunosuppression as part of the implantation protocol, CMV infection as documented by \>500 copies/ml in blood by PCR on two consecutive assays is an exclusion.

Primary outcomes:
measure: Survival Rate at End of 1 Year
timeFrame: 1 Year
measure: Survival Rate at End of 2 Year
timeFrame: 2 Year
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Duke University Medical Center, Pediatrics, Allergy & Immunology
name: John W. Sleasman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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. doi: 10.1182/blood-2003-08-2984. Epub 2004 Apr 20.
citation: 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.
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citation: Heimall J, Keller M, Saltzman R, Bunin N, McDonald-McGinn D, Zakai E, de Villartay JP, Moshous D, Ariue B, McCarthy EA, Devlin BH, Parikh S, Buckley RH, Markert ML. Diagnosis of 22q11.2 deletion syndrome and artemis deficiency in two children with T-B-NK+ immunodeficiency. J Clin Immunol. 2012 Oct;32(5):1141-4. doi: 10.1007/s10875-012-9741-9. Epub 2012 Aug 3.
citation: Ciupe SM, Devlin BH, Markert ML, Kepler TB. Quantification of total T-cell receptor diversity by flow cytometry and spectratyping. BMC Immunol. 2013 Aug 6;14:35. doi: 10.1186/1471-2172-14-35.
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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: Li B, Li J, Hsieh CS, Hale LP, Li YJ, Devlin BH, Markert ML. Characterization of cultured thymus tissue used for transplantation with emphasis on promiscuous expression of thyroid tissue-specific genes. Immunol Res. 2009;44(1-3):71-83. doi: 10.1007/s12026-008-8083-4.
citation: Gupton SE, McCarthy EA, Markert ML. Care of Children with DiGeorge Before and After Cultured Thymus Tissue Implantation. J Clin Immunol. 2021 Jul;41(5):896-905. doi: 10.1007/s10875-021-01044-0. Epub 2021 May 18.
citation: Markert ML, Gupton SE, McCarthy EA. Experience with cultured thymus tissue in 105 children. J Allergy Clin Immunol. 2022 Feb;149(2):747-757. doi: 10.1016/j.jaci.2021.06.028. Epub 2021 Aug 4.