Base Editing Hematopoietic Stem Cell and BE T Cell Gene Therapy for CD40L-HyperIgM Syndrome-Single Patient Study
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 1
- Locations
- 1
- Primary Endpoint
- Safety determined by toxicities related to the infusion of the Study Cell Products
Overview
Brief Summary
Background:
X-linked hyper-IgM (HIGM) syndrome is caused by a mutation in the CD40 ligand (CD40L) gene. People with this disease have white blood cells that do not work properly. These people are at risk of severe infections and autoimmune diseases. Researchers want to know if these base-edited stem cells and T cells can help people with CD40L-HIGM syndrome.
Objective:
To test base-edited stem cells and base-edited T cells in 1 person with CD40L-HIGM syndrome.
Eligibility:
A single male with CD40L-HIGM syndrome.
Design:
A single participant is planned to receive a single dose of edited stem cells and supportive treatment with edited T cells. Participant stem and T cells will undergo base editing to repair the mutation.
In preparation for the gene therapy, the participant will receive busulfan chemotherapy and alemtuzumab. After treatment, the participant will have follow-up visits every few months in the first 2 years after treatment. Long-term visits will continue annually for 15 years.
Detailed Description
Study Description:
This is a single participant gene therapy study to provide a participant with CD40L c.658C>T; p.Q220X-Hyper IgM syndrome with autologous base-edited hematopoietic stem/progenitor cells (HSPC) and base-edited T cells (BE T). The study hypothesis is that base edited HSPCs will be repaired efficiently and safely to restore CD40L expression and improve immune function long term. BE T cells will provide functional T cells to support subject against immunodeficiency and lymphopenia.
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan administered once daily for 2 days with a daily target AUC of 4500 micromol*min/L or a cumulative AUC of 9000 micromol*min/L (approximately 6 mg/kg) and serotherapy (alemtuzumab (Campath)) 10 mg/m^2 total dose divided over 3 days by subcutaneous injection on days -21, -20, and -19. Following infusion, the participant will be evaluated at months 3, 6, 9, 12, 18, 24. Long-term annual follow up will be performed on a separate protocol.
Base edited autologous T cells will be administered at 2 weeks following BE HSPC infusion that function as 'donor lymphocyte infusions' to protect the patient from the diseaserelated T-cell immunodeficiency and alemtuzumab-related lymphopenia. Subsequent doses of BE T cells may be infused monthly as indicated to achieve T cell reconstitution for treatment of infections.
Objectives:
-
Primary Objective: To determine the safety and efficacy of BE HSPC CD40L and BE T cells.
-
Secondary Objectives: To determine restoration of CD40L expression and immune function
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Exploratory Objectives:
-
Assess for potential unintended edits
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Kinetics of immune reconstitution
Endpoints:
-
Primary Endpoint:
-
Efficacy determined by percentages of corrected alleles
-
Safety determined by toxicities related to infusion of Study Cell Product
-
Secondary Endpoints:
-
Level of CD40L expression in peripheral blood T cells
-
IgG production
-
Response to immunization
-
Exploratory Endpoints:
-
Repeat WES at 24 months after study cell product infusion
-
Evaluate for gene correction levels in peripheral blood CD34s and isolated immune cell lineages
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 37 Years to 120 Years (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Base-edited hematopoietic stem and progenitor cells (Biological)
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Alemtuzumab (Drug)
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Sirolimus (Drug)
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Palifermin (Drug)
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Busulfan (Drug)
Single Arm Study
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
Intervention: Base-edited T lymphocyte cells (Biological)
Outcomes
Primary Outcomes
Safety determined by toxicities related to the infusion of the Study Cell Products
Time Frame: Through end of study
To determine the safety and efficacy of BE HSPC CD40L and BE T Cells
Efficacy determined by percentages of corrected alleles
Time Frame: Through end of study
To determine the safety and efficacy of BE HSPC CD40L and BE T Cells
Secondary Outcomes
- Level of CD40L expression in peripheral blood T cells(Through end of study)
- IgG production(Through end of study)
- Response to immunization(Through end of study)