DiGeorge Syndrome, Complete Typical DiGeorge Anomaly
Conditions
Keywords
Thymus Transplantation, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Primary immunodeficiency, DiGeorge Anomaly, Complete DiGeorge, Typical DiGeorge, Cultured Thymus Tissue Implantation (CTTI)
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.
Interventions
Cultured thymus tissue for implantation (CTTI) (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated thymus donors. Thymus tissue, the thymus donor, & thymus donor's birth mother were screened for safety. Approximately 2-3 weeks post-harvest thymus slices were implanted into the recipient's quadriceps. Dose was number of grams of cultured thymus tissue divided by the recipient's weight in kilograms. Minimum dose was 4 g/m2. Maximum dose 18g/m2. At time of CTTI, a skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. Post-CTTI, subjects followed by routine research immune evaluations, using blood samples for approximately 2 years.
Sponsors
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sumitomo Pharma Switzerland GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI) | 1 year post-CTTI | Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune Reconstitution Efficacy - Total CD3 T Cells | 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 | 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 | 1 year post-CTTI | The development of total CD8 T cells at one year as measured using flow cytometry |
| Survival at 2 Years Post-CTTI | 2 years post-CTTI | Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. |
| Immune Reconstitution Efficacy - Naive CD8 T Cells | 1 year post-CTTI | The development of naive CD8 T cells at one year as measured using flow cytometry |
| Immune Reconstitution Efficacy - Response to Mitogens | 1 year post-CTTI | The development of a T cell proliferative response to the mitogen phytohemagglutinin. |
| Thymus Allograft Biopsy | 2 to 3 months post-CTTI | Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells. |
| Immune Reconstitution Efficacy - Naive CD4 T Cells | 1 year post-CTTI | The development of naive CD4 T cells at one year as measured using flow cytometry |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cultured Thymus Tissue Implantation Cultured Thymus Tissue Implantation is done using allogeneic cultured postnatal thymus tissue from unrelated donors. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 7 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Cultured Thymus Tissue Implantation |
|---|---|
| Age, Categorical <=18 years | 26 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 153 days STANDARD_DEVIATION 102 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 26 |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 23 / 26 |
Outcome results
Primary
Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI)
Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
Time frame: 1 year post-CTTI
Population: Of the 26 participants, 2 subjects did not have cDGA (1 SCID and 1 FoxN1) and underwent CTTI as enrollment exceptions. The FoxN1 participant is included in the efficacy analysis, thus n=25. The SCID participant is not included in the efficacy analysis as CTTI cannot lead to T cell development in SCID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI) | 72 % of participants who survive to 1 year |
Secondary
Immune Reconstitution Efficacy - Naive CD4 T Cells
The development of naive CD4 T cells at one year as measured using flow cytometry
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if a T cell count was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Naive CD4 T Cells | 270 cells/mm3 |
Secondary
Immune Reconstitution Efficacy - Naive CD8 T Cells
The development of naive CD8 T cells at one year as measured using flow cytometry
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if a T cell count was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Naive CD8 T Cells | 65 cells/mm3 |
Secondary
Immune Reconstitution Efficacy - Response to Mitogens
The development of a T cell proliferative response to the mitogen phytohemagglutinin.
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if testing was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Response to Mitogens | 133000 counts/minute (cpm) |
Secondary
Immune Reconstitution Efficacy - Total CD3 T Cells
The development of total CD3 T cells at one year as measured using flow cytometry
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD3 T cell count was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Total CD3 T Cells | 770 cells/mm3 |
Secondary
Immune Reconstitution Efficacy - Total CD4 T Cells
The development of total CD4 T cells at one year as measured using flow cytometry
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD4 T cell count was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Total CD4 T Cells | 570 cells/mm3 |
Secondary
Immune Reconstitution Efficacy - Total CD8 T Cells
The development of total CD8 T cells at one year as measured using flow cytometry
Time frame: 1 year post-CTTI
Population: Data were only included on cDGA and FoxN1 participants for the 1 year time point if a CD8 T cell count was performed in the relevant time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Immune Reconstitution Efficacy - Total CD8 T Cells | 122 cells/mm3 |
Secondary
Survival at 2 Years Post-CTTI
Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
Time frame: 2 years post-CTTI
Population: Of the 26 participants, 2 subjects did not have cDGA (1 SCID and 1 FoxN1) and underwent CTTI as enrollment exceptions. The FoxN1 participant is included in the efficacy analysis, thus n=25. The SCID participant is not included in the efficacy analysis as CTTI cannot lead to T cell development in SCID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cultured Thymus Tissue Implantation | Survival at 2 Years Post-CTTI | 72 % of participants who survive to 2 years |
Secondary
Thymus Allograft Biopsy
Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.
Time frame: 2 to 3 months post-CTTI
Population: Data were only included on cDGA and FoxN1 participants if the participant had a biopsy of the thymus tissue implanted.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cultured Thymus Tissue Implantation | Thymus Allograft Biopsy | Evidence of thymopoiesis | 17 Participants |
| Cultured Thymus Tissue Implantation | Thymus Allograft Biopsy | Evidence of rejection | 1 Participants |
| Cultured Thymus Tissue Implantation | Thymus Allograft Biopsy | Inconclusive for thymopoiesis | 1 Participants |