Study Evaluating a Gene Therapy for IPEX Syndrome Through the Expression of FOXP3 on Deficient T Cells to Produce Tregs-like.

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.

• FOXP3-T4 drug product (Genetic): Each patient will receive a single IV infusion of FOXP3-T4, autologous gene-modified CD4+ T-transduced ex vivo with a self-inactivating lentiviral vector (LV-EF1a.FOXP3-LNGFR)
• ILT-101 (Drug), also known as Adeleuskin or IL2: The first two patients included in the study will not receive IL-2 treatment. The others will receive the first injection the FOXP3-T4 treatment and if needed IL2-treatment. For IL2 treatment, patients will receive a daily dose for 5 days, followed by an administration per week for 3 months (ILT-101)

Primary outcomes

• Frequency of clinical AEs and pathological variations of laboratory parameters [Up to 24 months post-infusion]: Number of clinical AEs
• Severity of clinical AEs and pathological variations of laboratory parameters [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 [Up to 24 months post-infusion]: This is measured via Vector Insertion Site Analysis (VISA)
• Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance [Beyond 3 months to 24 months post-infusion]: This is measured by proliferation of LNGFR+ cells
• Detection of Replication-Competent Lentivirus (RCL) [Up to 24 months post-infusion]
• Persistence of recirculating LNGFR+among CD4+ T cells [at 3 months post-infusion]: Percentage of LNGFR+ among CD4+ T cells

Secondary outcomes

• Persistence of FOXP3-T4 Cells [Up to 24 months post-infusion]: Persistence of recirculating LNGFR among CD4+ T cells
• Phenotyping [Up to 24 months post-infusion]: Deeper phenotyping of FOXP3-T4 (CD4+LNGFR+ CD25+ FOXP3+ CD127low)
• Vector Copy Number (VCN) Analysis [Up to 24 months post-infusion]: Quantification of the transgene copy number (VCN) on drug product and on sorted T-CD4+
• 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]: Evaluated by NGS before and after the treatment with FOXP3-T4
• 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]: Diminution of the skin lesions severity
• Organ-Specific Remission: Skin disease [Up to 24 months post-infusion]: Diminution of inflammation in the skin biopsy
• Organ-Specific Remission: Endocrine System Function [Up to 24 months post-infusion]: Evaluation of the functions of endocrine glands
• Organ-Specific Remission: Endocrine System Function [Up to 24 months post-infusion]: Reduction of insulin dose administrered
• Organ-Specific Remission: Endocrine System Function [Up to 24 months post-infusion]: Reduction of HBA1C
• Organ-Specific Remission: Renal function [Up to 24 months post-infusion months]: Improvement of creatine and creatine clearance
• Organ-Specific Remission: Renal function [Up to 24 months post-infusion months]: Improvement of proteinuria
• Organ-Specific Remission: Renal function [Up to 24 months post-infusion months]: Improvement of tubular effect
• Organ-Specific Remission: Digestive System [Up to 24 months post-infusion months]: Change in the weight curve
• Organ-Specific Remission: Digestive System [Up to 24 months post-infusion months]: Change in diarrhea incidence
• Organ-Specific Remission: Digestive System [Up to 24 months post-infusion months]: Decrease of fecal calprotectin
• Organ-Specific Remission: Musculoskeletal System [Up to 24 months post-infusion months]: Improvement of arthritis evaluated by physical examination
• Organ-Specific Remission: Respiratory Function [Up to 24 months post-infusion months]: Improvement of asthma evaluated by physical examination
• Organ-Specific Remission: General status [Up to 24 months post-infusion months]: Improvement of performance status : Lansky and Karnofsky scores range from 100 to 10
• Organ-Specific Remission: Blood count [Up to 24 months post-infusion months]: Presence of autoimmune hemolytic anemia
• Organ-Specific Remission: Blood count [Up to 24 months post-infusion months]: Presence of thrombocytopenia
• Organ-Specific Remission: Eye [Up to 24 months post-infusion months]: Improvement of blepheratis evaluated by physical examination.
• Reduction of Concomitant Therapy [Up to 24 months]: Reduction of corticosteroid therapy or immunosuppressive treatment

Sex: Male, ages: 1 Year to 45 Years

Inclusion Criteria:

* 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

Exclusion Criteria:

* 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.

• Delville M, Bellier F, Leon J, Klifa R, Lizot S, Vincon H, Sobrino S, Thouenon R, Marchal A, Garrigue A, Olivre J, Charbonnier S, Lagresle-Peyrou C, Amendola M, Schambach A, Gross D, Lamarthee B, Benoist C, Zuber J, Andre I, Cavazzana M, Six E. A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome. Blood. 2021 Apr 29;137(17):2326-2336. doi: 10.1182/blood.2020009187. PMID 33545713

• Emmanuelle SIX, MD, PhD, Study chair, Institut Imagine

NIH grants: 2025