The Immune Dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome is a Primary Immunodeficiency Caused by Pathogenic Variants in Forkhead Box Protein 3
Conditions
Keywords
Autoimmune diseases, Genetic diseases, Gene therapy, Lentiviral vector, Immune dysregulation Polyendocrinopathy Enteropathy X-linked, Autoimmunity-Immunodeficiency Syndrome, Forkhead Box Protein 3, Low-dose IL-2
Brief summary
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.
Detailed description
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.
Interventions
GENETICFOXP3-T4 drug product
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)
DRUGILT-101
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)
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
1 Years to 45 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: Endocrine System Function | Up to 24 months post-infusion | Evaluation of the functions of endocrine glands |
| Organ-Specific Remission: Renal function | Up to 24 months post-infusion months | Improvement of creatine and creatine clearance |
| Organ-Specific Remission: Digestive System | Up to 24 months post-infusion months | Change in the weight curve |
| 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: 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 |
Countries
France
Contacts
CONTACTMarina CAVAZZANA, MD, PhD
CONTACTAline DECHANET, Project Manager
STUDY_CHAIREmmanuelle SIX, MD, PhD
Institut Imagine
Outcome results
None listed