A Phase I/II Open-label, Non-randomized, Monocentric, Single-arm Study Evaluating the Safety and Efficacy of Induced CD4+ Treg by LV Vector Transduction Expressing the FOXP3 cDNA (FOXP3-T4) in Patients With IPEX Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Frequency of clinical AEs and pathological variations of laboratory parameters
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficacy of FOXP3-T4 (an autologous gene therapy) alone or in combination with low-dose IL-2 for the treatment of IPEX syndrome. The therapy involves the transplantation of autologous CD4+ T-cells transduced ex vivo with the LV-EF1a-FOXP3-LNGFR lentiviral vector. The study follows a staggered approach: the first two patients will receive FOXP3-T4 monotherapy. Subsequent patients will receive FOXP3-T4 followed if needed by low-dose IL-2 treatment consisting of a daily dose for 5 days, then weekly administrations for 3 months.
The study aims to stabilize autoimmune manifestations and potentially cure the underlying disease, ultimately allowing for the discontinuation of ongoing immunosuppressive treatments.
详细描述
IPEX syndrome is a primary immunodeficiency caused by hemizygous mutations in the gene FOXP3, which encodes an essential transcription factor required to maintain immunological tolerance by thymus-derived regulatory T (Treg) cells. The most common presentation suggestive of the diagnosis of IPEX syndrome is the classical triad of enteropathy, type I diabetes (TID), and eczema in neonatal onset. Still, it is now well established that IPEX syndrome comprises a broad spectrum of clinical manifestations with different degrees of severity and evolution.
Currently, the only curative treatment for the severe form is allogeneic hematopoietic stem cell transplantation (HSCT). However, because of its significant toxicity, it can be proposed only for more severe presentations and when an HLA identical donor is available. Moreover, the post-HSCT prognosis is also linked to prior disease activity and organ failures.
This clinical study aims to assess a new therapeutical strategy consisting of the conversion of the IPEX patient's CD4+T-cells into functional Treg-like cells by transducing them with an optimized bidirectional lentivirus vector expressing human FOXP3 and a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR) allowing the selection of the transduced cells. To favour Treg-like cells engraftment and expansion, the FOXP3-T4 infusion may be combined with subcutaneous injection of low-dose IL-2, if needed. Injecting FOXP3-T4 T-reg-like cells into IPEX patients is expected to stably improve the autoimmune manifestations and even cure the underlying disease, allowing the ongoing immunosuppressive treatments to be stopped.
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
- 1 Year 至 45 Years（Child, Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male patients only
- •Patients aged from 1 - 45 years of age (the first three patients will be aged between 10 - 45 years of age)
- •Patient with IPEX syndrome caused by mutation of the FOXP3 gene
- •Patients are eligible from the second line of treatment onward, even those under controlled disease
- •Patient with recurrent IPEX symptoms, under immune suppressive medications
- •Patient for whom HSCT is not feasible or when no suitable compatible donor is available
- •Patients who have had prior allogeneic blood stem cell transplantation (HSCT) with engraftment failure defined as no intake of donor cells
- •Patient or parental, guardian's patient signed informed consent
- •Male participants of reproductive potential with a partner of childbearing potential (WOCBP): willing to use an effective method of contraception during the trial and for at least 12 months post-infusion
- •Affiliation to a French or European social security scheme
排除标准
- •Unwillingness to return for follow-up during the 2-year study and during the 15 years of long term follow up study.
- •Patient with short life expectancy
- •Patient on AME (state medical aid) (unless exemption from affiliation).
- •Diagnosis of a significant psychiatric disorder of the patient that could seriously impede the ability to participate in the study.
- •Eligible for an HLA matched sibling or matched unrelated donor blood stem cell transplant (HLA 10/10) and be willing to undergo transplant.
- •Patients with uncontrolled or ongoing active infections.
- •HIV-1 or 2 or HTLV-1 infections.
- •Patients with severe IPEX clinical presentation needing a rapid allogeneic HSCT treatment within 3 months.
- •Patients with known history of hypersensitivity to IL-2 or any component of the formulation (mannitol, sodium lauryl sulfate, monosodium phosphate dehydrate, disodium phosphate dehydrate, glucose.
研究组 & 干预措施
FOXP3-T4 drug product
FOXP3-T4 is a genetically modified cell therapy product consisting of autologous CD4+ T-cells transduced ex vivo with a self-inactivating bidirectional lentiviral vector (LV-EF1a-FOXP3-LNGFR) expressing the FOXP3 and LNGFR cDNAs.
干预措施: FOXP3-T4 drug product (Genetic)
FOXP3-T4 drug product
FOXP3-T4 is a genetically modified cell therapy product consisting of autologous CD4+ T-cells transduced ex vivo with a self-inactivating bidirectional lentiviral vector (LV-EF1a-FOXP3-LNGFR) expressing the FOXP3 and LNGFR cDNAs.
干预措施: ILT-101 (Drug)
结局指标
主要结局
Frequency of clinical AEs and pathological variations of laboratory parameters
时间窗: Up to 24 months post-infusion
Number of clinical AEs
Severity of clinical AEs and pathological variations of laboratory parameters
时间窗: Up to 24 months post-infusion
Grading will be performed according to the CTCAE (Common Terminology Criteria for Adverse Events) current version. Severity is rated on a scale of Grade 1 (Mild) to Grade 5 (Death).
Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance
时间窗: Up to 24 months post-infusion
This is measured via Vector Insertion Site Analysis (VISA)
Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance
时间窗: Beyond 3 months to 24 months post-infusion
This is measured by proliferation of LNGFR+ cells
Detection of Replication-Competent Lentivirus (RCL)
时间窗: Up to 24 months post-infusion
Persistence of recirculating LNGFR+among CD4+ T cells
时间窗: at 3 months post-infusion
Percentage of LNGFR+ among CD4+ T cells
次要结局
- Persistence of FOXP3-T4 Cells(Up to 24 months post-infusion)
- Phenotyping(Up to 24 months post-infusion)
- Vector Copy Number (VCN) Analysis(Up to 24 months post-infusion)
- Immunophenotyping T and B cells if no change is detected from the baseline (e.g. before treatment), the immunological phenotype(Beyond 3 months to 24 months post-infusion)
- TCR repertoire(At 3 months, 12 months and 24 months, post-infusion)
- Autoantibodies dosage(At 3 months, 6 months, 12 months and 24 months post-infusion)
- Organ-Specific Remission: Skin disease(Up to 24 months post-infusion)
- Organ-Specific Remission: Endocrine System Function(Up to 24 months post-infusion)
- Organ-Specific Remission: Renal function(Up to 24 months post-infusion months)
- Organ-Specific Remission: Digestive System(Up to 24 months post-infusion months)
- Organ-Specific Remission: Musculoskeletal System(Up to 24 months post-infusion months)
- Organ-Specific Remission: Respiratory Function(Up to 24 months post-infusion months)
- Organ-Specific Remission: General status(Up to 24 months post-infusion months)
- Organ-Specific Remission: Blood count(Up to 24 months post-infusion months)
- Organ-Specific Remission: Eye(Up to 24 months post-infusion months)
- Reduction of Concomitant Therapy(Up to 24 months)