Study Evaluating a Gene Therapy for IPEX Syndrome Through the Expression of FOXP3 on Deficient T Cells to Produce Tregs-like. (THERIPEX)
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
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.
연구 개요
상태
상세 설명
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.
연구 유형
등록 (추정된)
단계
- 2 단계
- 1단계
연락처 및 위치
연구 연락처
- 이름: Marina CAVAZZANA, MD, PhD
- 전화번호: + 33 01 44 49 50 68
- 이메일: m.cavazzana@aphp.fr
연구 연락처 백업
- 이름: Aline DECHANET, Project Manager
- 전화번호: +33 01 44 38 17 11
- 이메일: aline.dechanet@aphp.fr
연구 장소
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Île-de-France Region
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Paris, Île-de-France Region, 프랑스, 75015
- Department of Biotherapy, Hopital Necker Enfants malades
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연락하다:
- Marina CAVAZZANA, MD, PHD
- 전화번호: +33 01 44 49 50 68
- 이메일: m.cavazzana@aphp.fr
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참여기준
자격 기준
공부할 수 있는 나이
- 어린이
- 성인
건강한 자원 봉사자를 받아들입니다
설명
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.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: 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.
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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)
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)
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Frequency of clinical AEs and pathological variations of laboratory parameters
기간: Up to 24 months post-infusion
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Number of clinical AEs
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Up to 24 months post-infusion
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Severity of clinical AEs and pathological variations of laboratory parameters
기간: Up to 24 months post-infusion
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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).
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Up to 24 months post-infusion
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Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance
기간: Up to 24 months post-infusion
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This is measured via Vector Insertion Site Analysis (VISA)
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Up to 24 months post-infusion
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Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance
기간: Beyond 3 months to 24 months post-infusion
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This is measured by proliferation of LNGFR+ cells
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Beyond 3 months to 24 months post-infusion
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Detection of Replication-Competent Lentivirus (RCL)
기간: Up to 24 months post-infusion
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Up to 24 months post-infusion
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Persistence of recirculating LNGFR+among CD4+ T cells
기간: at 3 months post-infusion
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Percentage of LNGFR+ among CD4+ T cells
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at 3 months post-infusion
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Persistence of FOXP3-T4 Cells
기간: Up to 24 months post-infusion
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Persistence of recirculating LNGFR among CD4+ T cells
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Up to 24 months post-infusion
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Phenotyping
기간: Up to 24 months post-infusion
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Deeper phenotyping of FOXP3-T4 (CD4+LNGFR+ CD25+ FOXP3+ CD127low)
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Up to 24 months post-infusion
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Vector Copy Number (VCN) Analysis
기간: Up to 24 months post-infusion
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Quantification of the transgene copy number (VCN) on drug product and on sorted T-CD4+
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Up to 24 months post-infusion
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Immunophenotyping T and B cells if no change is detected from the baseline (e.g. before treatment), the immunological phenotype
기간: Beyond 3 months to 24 months post-infusion
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Beyond 3 months to 24 months post-infusion
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TCR repertoire
기간: At 3 months, 12 months and 24 months, post-infusion
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Evaluated by NGS before and after the treatment with FOXP3-T4
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At 3 months, 12 months and 24 months, post-infusion
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Autoantibodies dosage
기간: At 3 months, 6 months, 12 months and 24 months post-infusion
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At 3 months, 6 months, 12 months and 24 months post-infusion
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Organ-Specific Remission: Skin disease
기간: Up to 24 months post-infusion
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Diminution of the skin lesions severity
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Up to 24 months post-infusion
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Organ-Specific Remission: Skin disease
기간: Up to 24 months post-infusion
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Diminution of inflammation in the skin biopsy
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Up to 24 months post-infusion
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Organ-Specific Remission: Endocrine System Function
기간: Up to 24 months post-infusion
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Evaluation of the functions of endocrine glands
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Up to 24 months post-infusion
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Organ-Specific Remission: Endocrine System Function
기간: Up to 24 months post-infusion
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Reduction of insulin dose administrered
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Up to 24 months post-infusion
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Organ-Specific Remission: Endocrine System Function
기간: Up to 24 months post-infusion
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Reduction of HBA1C
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Up to 24 months post-infusion
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Organ-Specific Remission: Renal function
기간: Up to 24 months post-infusion months
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Improvement of creatine and creatine clearance
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Up to 24 months post-infusion months
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Organ-Specific Remission: Renal function
기간: Up to 24 months post-infusion months
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Improvement of proteinuria
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Up to 24 months post-infusion months
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Organ-Specific Remission: Renal function
기간: Up to 24 months post-infusion months
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Improvement of tubular effect
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Up to 24 months post-infusion months
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Organ-Specific Remission: Digestive System
기간: Up to 24 months post-infusion months
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Change in the weight curve
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Up to 24 months post-infusion months
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Organ-Specific Remission: Digestive System
기간: Up to 24 months post-infusion months
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Change in diarrhea incidence
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Up to 24 months post-infusion months
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Organ-Specific Remission: Digestive System
기간: Up to 24 months post-infusion months
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Decrease of fecal calprotectin
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Up to 24 months post-infusion months
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Organ-Specific Remission: Musculoskeletal System
기간: Up to 24 months post-infusion months
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Improvement of arthritis evaluated by physical examination
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Up to 24 months post-infusion months
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Organ-Specific Remission: Respiratory Function
기간: Up to 24 months post-infusion months
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Improvement of asthma evaluated by physical examination
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Up to 24 months post-infusion months
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Organ-Specific Remission: General status
기간: Up to 24 months post-infusion months
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Improvement of performance status : Lansky and Karnofsky scores range from 100 to 10
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Up to 24 months post-infusion months
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Organ-Specific Remission: Blood count
기간: Up to 24 months post-infusion months
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Presence of autoimmune hemolytic anemia
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Up to 24 months post-infusion months
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Organ-Specific Remission: Blood count
기간: Up to 24 months post-infusion months
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Presence of thrombocytopenia
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Up to 24 months post-infusion months
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Organ-Specific Remission: Eye
기간: Up to 24 months post-infusion months
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Improvement of blepheratis evaluated by physical examination.
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Up to 24 months post-infusion months
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Reduction of Concomitant Therapy
기간: Up to 24 months
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Reduction of corticosteroid therapy or immunosuppressive treatment
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Up to 24 months
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공동 작업자 및 조사자
수사관
- 연구 의자: Emmanuelle SIX, MD, PhD, Institut Imagine
간행물 및 유용한 링크
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
키워드
추가 관련 MeSH 약관
기타 연구 ID 번호
- APHP251137
- 2025-523305-15-00 (씨티스)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
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