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

Official title

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

Overview

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

• Genetic FOXP3-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)
• Drug ILT-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)

Primary outcome measures

• Frequency of clinical AEs and pathological variations of laboratory parameters [Time frame: Up to 24 months post-infusion]
• Severity of clinical AEs and pathological variations of laboratory parameters [Time frame: Up to 24 months post-infusion]
• Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance [Time frame: Up to 24 months post-infusion]
• Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance [Time frame: Beyond 3 months to 24 months post-infusion]
• Detection of Replication-Competent Lentivirus (RCL) [Time frame: Up to 24 months post-infusion]
• Persistence of recirculating LNGFR+among CD4+ T cells [Time frame: at 3 months post-infusion]

Secondary outcome measures (12)

• Persistence of FOXP3-T4 Cells [Time frame: Up to 24 months post-infusion]
• Phenotyping [Time frame: Up to 24 months post-infusion]
• Vector Copy Number (VCN) Analysis [Time frame: 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 [Time frame: Beyond 3 months to 24 months post-infusion]
• TCR repertoire [Time frame: At 3 months, 12 months and 24 months, post-infusion]
• Autoantibodies dosage [Time frame: At 3 months, 6 months, 12 months and 24 months post-infusion]
• Organ-Specific Remission: Skin disease [Time frame: Up to 24 months post-infusion]
• Organ-Specific Remission: Skin disease [Time frame: Up to 24 months post-infusion]
• Organ-Specific Remission: Endocrine System Function [Time frame: Up to 24 months post-infusion]
• Organ-Specific Remission: Endocrine System Function [Time frame: Up to 24 months post-infusion]
• Organ-Specific Remission: Endocrine System Function [Time frame: Up to 24 months post-infusion]
• Organ-Specific Remission: Renal function [Time frame: Up to 24 months post-infusion months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• Department of Biotherapy, Hopital Necker Enfants malades — Paris

Publications

• 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 PMID 33545713

Identifiers

NCT: NCT07697118 · APHP251137 · 2025-523305-15-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗