A Pilot Feasibility Study of Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants Using a Self-Inactivating Lentiviral Vector to Transduce Autologous CD34+ Hematopoietic Cells
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 28
- 试验地点
- 3
- 主要终点
- Number of patients with successful reconstitution
研究概览
简要总结
SCID-X1 is a genetic disorder of blood cells caused by DNA changes in a gene that is required for the normal development of the human immune system. The purpose of this study is to determine if a new method, called lentiviral gene transfer, can be used to treat SCID-X1. This method involves transferring a normal copy of the common gamma chain gene into the participant's bone marrow stem cells. The investigators want to determine if the procedure is safe, whether it can be done according to the methods they have developed, and whether the procedure will provide a normal immune system for the patient. It is hoped that this type of gene transfer may offer a new way to treat children with SCID-X1 that do not have a brother or sister who can be used as a donor for stem cell transplantation.
详细描述
Bone marrow CD34+ cells will be obtained in the operating room, transduced with the lentiviral vector that contains a normal copy of the γc gene, and reinfused without any myeloreductive conditioning. Participants will be monitored for hematopoietic recovery from busulfan and for severe adverse events for 42 days post gene therapy. The primary endpoint assessing the efficacy of this approach will be T-cell immune reconstitution 52 weeks (± 4) weeks after transplantation. Continued and detailed evaluation of all aspects of immune reconstitution, protocol-related toxicity, and retroviral integration sites will also be performed. This study will evaluate the first use of a SIN lentiviral vector for the treatment of SCID-X1 and may lead to a new form of therapy that could be applied to the majority of newly diagnosed patients.
OBJECTIVES
Assess the safety, feasibility and efficacy of lentiviral gene transfer in newly diagnosed SCID-X1 patients transplanted with autologous CD34+ cells that have been transduced with a self-inactivating lentiviral vector (CL20-i4-EF1α-hγc-OPT) expressing a γc gene.
Primary Objective 1: Evaluate the safety and feasibility of infusing at least 1 million transduced CD34+ cells per kilogram of body weight in SCID-X1 infants.
Primary Objective 2: Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks (± 4 weeks) after transplantation. Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 24 Months（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •* Treatment Eligibility Criteria:
- •Age <2 years at the time of enrollment.
- •No prior therapy with allogeneic stem cell transplantation.
- •A clinical diagnosis of SCID-X1 documented in the medical record.
- •A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA.
- •Age > 2 months to < 1 year of age at the time of busulfan administration.
- •Less than 300 CD3+ T-cells by flow cytometry or higher if evidence of maternal engraftment as supported by peripheral blood FISH analysis for XY and XX.
- •Lymphocyte proliferation to phytohemagglutinin (PHA) <10% of the lower limit of normal for the laboratory.
排除标准
- •Availability of a HLA matched sibling for allogeneic transplantation
- •Prior therapy with allogeneic stem cell transplantation
- •Positive for HIV infection by genome PCR
- •Presence of a medical condition indicating that survival will be less than 16 weeks such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
- •The presence of any medical contraindications to general anesthesia and bone marrow harvest by aspiration
- •A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care.
研究组 & 干预措施
Treatment
Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. Cells will be isolated and purified utilizing the CliniMacs device. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-i4-EF1α-hγc-OPT) and then the transduced cells will be reinfused back into the patient. Participants will receive a conditioning regimen of busulfan 3 days prior and 2 days prior to infusion of vector-corrected cells.intervention: CL20-i4-EF1α-hγc-OPT
干预措施: CL20-i4-EF1α-hγc-OPT (Genetic)
Treatment
Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. Cells will be isolated and purified utilizing the CliniMacs device. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-i4-EF1α-hγc-OPT) and then the transduced cells will be reinfused back into the patient. Participants will receive a conditioning regimen of busulfan 3 days prior and 2 days prior to infusion of vector-corrected cells.intervention: CL20-i4-EF1α-hγc-OPT
干预措施: Busulfan (Drug)
Treatment
Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. Cells will be isolated and purified utilizing the CliniMacs device. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-i4-EF1α-hγc-OPT) and then the transduced cells will be reinfused back into the patient. Participants will receive a conditioning regimen of busulfan 3 days prior and 2 days prior to infusion of vector-corrected cells.intervention: CL20-i4-EF1α-hγc-OPT
干预措施: CliniMacs (Device)
结局指标
主要结局
Number of patients with successful reconstitution
时间窗: 42 days post gene transfer
Reconstitution with transduced cells defined as detection of vector-marked peripheral blood cells by real time PCR at or above 0.02% VCN in total WBC.
Number of patients with adequate cell collection and processing
时间窗: Day 0
The number of patients who underwent no more than two bone marrow harvests and cryopreservation of at least 1.0 million cells/kg following vector transduction.
Number of patients with adequate neutrophil count recovery after busulfan conditioning
时间窗: Day 42 post gene transfer
Adequate recovery is defined as absolute neutrophil count (ANC) \>500 cells/μl by day +42 unless the patient is neutropenic prior to busulfan administration.
Number of patients without Grade 4 adverse event (AE)
时间窗: 42 days post gene transfer
The number of patients experiencing no directly related grade 4 or greater adverse event.
Number of patients with treatment failure
时间窗: 42 days post gene transfer
Treatment failure will be defined as lack of adequate cell collection and processing, lack of neutrophil count recovery by day +42, occurrence of grade 4 or greater toxicities by day +42, and/or lack of detection of \>0.02% transduced cells in peripheral blood by day +42 post gene transfer.
次要结局
未报告次要终点