CD4^LVFOXP3 in Participants With IPEX

Phase 1 Study of Autologous CD4^LVFOXP3 in Participants With Immune Dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) Syndrome

This first-in-human, Phase 1 clinical trial will test the feasibility of the manufacturing and the safety of the administration of CD4^LVFOXP3 in up to 30 evaluable human participants with IPEX and evaluate the impact of the CD4^LVFOXP3 infusion on the disease.

Study Overview

• Status: Recruiting
• Conditions: IPEX
• Intervention / Treatment: Biological: CD4^LVFOXP3

Detailed Description

Treatment with CD4^LVFOXP3 is expected to replace the defective Treg cells of the participants, and restore control of the immune system and therefore ameliorate symptoms of IPEX.

We expect to learn the following from this study:

1. That CD4^LVFOXP3 can be consistently produced and be of expected quality to be used in humans,
2. That CD4^LVFOXP3 are safe in children and young adults with IPEX, and determine its effects, both good and bad,
3. That CD4^LVFOXP3 can improve overall health and allow reduction of medication/s.

This Phase 1 (feasibility and safety) trial will gather data about CD4^LVFOXP3 in vivo persistency and early signs of impact on symptoms of IPEX.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rosa Bacchetta, MD; Phone Number: 650-498-8369; Email: rosab@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Lucile Packard Children's Hospital
      • Sub-Investigator: Rajni Agarwal, MD
      • Contact: SCGT Clinical Trials Program; Email: DL-SCTIntakeCoordinators@stanfordchildrens.org
      • Principal Investigator: Jessie Alexander

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Body weight greater than 8 kg, unless assessed as able to tolerate leukapheresis
• FOXP3 gene mutation
• Medical history of progressive symptoms of IPEX with persistency of some symptoms and/or signs requiring immune suppressive medication. The participant may or may not be on immunosuppression at time of starting the study.
• Uncontrolled IPEX disease but unable to tolerate immune suppressive medication
• Recurrent IPEX symptoms, requiring immune suppressive medications, in participants who have had prior allogeneic (allo) blood stem cell transplantation (HSCT).
• ≥ 50% Performance rating on Lansky/Karnofsky Scale
• Organ and marrow function within acceptable levels of function
• Absence of ongoing infections
• Must be able to consent if an adult

Exclusion Criteria:

• Medical instability
• Less than 6 months life expectancy
• Inability to meet limits for steroid dosing
• Eligible for an HLA matched sibling or matched unrelated donor blood stem cell transplant, and be willing to undergo transplant.
• Unrelated or comorbid disease
• Allergy to any study medication, product, or intervention
• Currently receiving another experimental treatment
• History of malignancy, unless disease free for at least 2 years, with the exception of non melanoma skin cancer or carcinoma in situ

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A (≥12 years); The first participant in Dose Level 1 will be administered 1.0 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in the first participant, the following participants in Dose Level 1 will be administered the same dose of 1.0 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 1, participants will be enrolled into Dose Level 2 and administered 3 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.	Biological: CD4^LVFOXP3; Infusion of autologous CD4+ T cells that have undergone lentiviral-mediated gene transfer of: i) healthy human FOXP3 gene leading to persistent high FOXP3 expression and acquisition of Treg-like cell function; and ii) human CD271 surface marker gene that allows tracking and quantification of the CD4^LVFOXP3 in the blood.; Other Names: CD4^LVFOXP3 Treg-like cells
Experimental: Cohort B (<12 years); Participants in Cohort B will always follow treatment of participants in Cohort A for the same dose level. Cohort B will start at Dose Level 2 and be administered 3 x 10^6 CD4^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10^6 CD4^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.	Biological: CD4^LVFOXP3; Infusion of autologous CD4+ T cells that have undergone lentiviral-mediated gene transfer of: i) healthy human FOXP3 gene leading to persistent high FOXP3 expression and acquisition of Treg-like cell function; and ii) human CD271 surface marker gene that allows tracking and quantification of the CD4^LVFOXP3 in the blood.; Other Names: CD4^LVFOXP3 Treg-like cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Find the safe maximum tolerated dose	No more than 1 out of 6 participants may experience a related dose limiting toxicity or treatment emergent adverse events.	Up to 60 days post-infusion for each participant
Meet target cell number for dose manufacturing	No more than two products fail the target cell dose and established release criteria.	Time at release from manufacturing (by Day 0 [infusion day] for each participant)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Diarrhea incidence	Stool Diary records - extent of diarrhea as measured by frequency and volume of stools, and the presence or absence of blood and/or mucus, and stool studies at specified time points (for all ages).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (daily for the first month followed by monthly at Month 2, 3, 6, 9, 12)
Change in GI Symptoms - Gastrointestinal Symptoms Rating Scale	Gastrointestinal Symptoms Rating Scale (GSRS) (for patients ≥12 years old).	Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4, Month 6, Month 12)
Change in Body Mass Index (BMI)	BMI measured as kg/m^2.	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3, Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in age-specific percentiles of height		Baseline (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Month 12)
Change in age-specific percentiles of bodyweight		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3, Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in Bilirubin levels		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)
Change in Liver Enzyme - Alanine Transaminase (ALT)		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)
Change in Liver Enzyme - Aspartate Transaminase (AST)		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)
Change in Liver Enzyme - Alkaline Phosphatase (ALP)		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)
Change in Liver Enzyme - Gamma Glutyltranspeptidase (GGT)		Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 2, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12)
Skin Disease (EASI) - Changes from Baseline/ Pre-infusion	Scoring of areas of involvement in each anatomical region (area), calculation of intensity using Eczema Area and Severity Index (EASI).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)
Skin Disease (POEM) - Changes from Baseline/ Pre-infusion	Scoring of areas of involvement in each anatomical region (area), calculation of intensity using Patient oriented eczema measure (POEM).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)
Skin Disease (PASI) - Changes from Baseline/ Pre-infusion	Changes in the extent (%) and severity of skin lesions and their complications (i.e. infections, atrophy, itching) using Psoriasis Area and Severity Index (PASI).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)
Skin Disease (MTLSS) - Changes from Baseline/ Pre-infusion	Changes in the extent (%) and severity of skin lesions and their complications (i.e. infections, atrophy, itching) using Modified Total Lesional Sign Score (MTLSS).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)
Change in skin barrier function	Biophysical Skin Evaluation: Skin measurement of transepidermal water loss to monitor skin barrier function and erythema	Baseline (up to 60 days before infusion of CD4^LVFOXP3), through post-infusion (Day 1; Week 1, 2, 3, 4; Month 3, 6 and 12)
Change in Hemolytic Anemia (RBC)	Measurement of the number of red blood cells (Complete Blood Counts with Differential [CBCD]).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3; Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in Hemolytic Anemia (Reticulocyte)	Measurement of the number of reticulocytes.	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3; Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in Thrombocytopenia	Measure the number of platelets (Complete Blood Counts with Differential (CBCD)).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3; Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in Neutropenia	Measure the number of neutrophils (Complete Blood Counts with Differential [CBCD]).	Baseline (up to 60 days before infusion of CD4^LVFOXP3), pre-infusion through post-infusion (Day 1, 2, 3; Week 1, 2, 3, 4; Month 2, 3, 6, 9, 12)
Change in C-peptide - Type 1 diabetes Pre-onset		Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
Change in HbA1c - Type 1 diabetes Pre-onset		Baseline taken 60-30 days before infusion of CD4^LVFOXP3; Post-infusion (Week 4, Month 3, 6 and 12).
Change in Daily insulin requirement - Type 1 diabetes monitoring	Mean daily insulin use recorded over 7 consecutive days preceding each evaluation timepoint for patients with Type 1 Diabetes.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
Change in hyper-/hypo-glycemic events - Type 1 diabetes monitoring	Continuous glucose monitoring (CGM) metrics to log episodes of hyper/hypoglycemic events.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3 and post-infusion (over 7 consecutive days preceding each study visit);
Change in Creatinine as a measure of Kidney Function	Measure kidney functional parameters, i.e., creatinine, in the blood and urine.	Baseline taken 60-30 days before infusion of CD4^LVFOXP3, Pre-infusion, Week 1, 2, 3, 4; Month 2, 3, 6, 9 and 12
Change in PedsQL General Well-Being Scale - Quality of Life		Pre-Infusion; Month 6, 12
Change in PedsQL Generic Core Scale - Quality of Life		Pre-Infusion; Month 6, 12
Change in PedsQL Gastrointestinal Symptoms Scale - Quality of Life	Measured with Gastrointestinal Symptoms Scale: minimum value = 0 (never a problem), maximum value = 4 (almost always a problem). Higher scores mean a worse outcome.	Pre-Infusion; Month 6, 12
Disease-free Survival - Changes from Baseline	The length of time from cell infusion to the point at which the participant survives without any new or worsening of existing signs or symptoms of disease. The data will be compared with historical disease-free survival probability. Probability of disease-free survival will be computed with the use of Kaplan-Meier estimator.	Up to 15 years
Overall Survival - Changes from Baseline	Participant survival	Up to 15 years
Change in INR level	International normalized ratio (INR) to determine prothrombin time.	Baseline/screening (up to 60 days before infusion of CD4^LVFOXP3) through post-infusion (Week 4; Month 3, 6, 12)
Change in Autoantibody Profile	Measure autoantibodies to organs involved in the disease (participant-specific): anti-insulin (IAA), anti-islet antigens (IA), anti-glutamic acid decarboxylase (GAD), anti-zinc transporter8 (ZNT8), anti-islet cells (ICA), anti-liver kidney microsome (LKM), anti-thyroperoxidase (TPO), anti-thyroglobulin (TG), anti-enterocytes, anti-SMA	Screening/ Baseline, Post-infusion (Month 6 and 12)

Collaborators and Investigators

• Sponsor: Bacchetta, Rosa, MD
• Collaborators: California Institute for Regenerative Medicine (CIRM)
• Investigators: Principal Investigator: Jessie Alexander, MD, Stanford University

Publications and helpful links

General Publications

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• Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, Choe YH, Cancrini C, Corrente S, Ciccocioppo R, Cecconi M, Zuin G, Discepolo V, Sartirana C, Schmidtko J, Ikinciogullari A, Ambrosi A, Roncarolo MG, Olek S, Bacchetta R. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012 Feb;38(1):49-58. doi: 10.1016/j.jaut.2011.12.009. Epub 2012 Jan 20.
• Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, Nademi Z, Slatter MA, Ulloa ER, Shcherbina A, Roppelt A, Worth A, Silva J, Aiuti A, Murguia-Favela L, Speckmann C, Carneiro-Sampaio M, Fernandes JF, Baris S, Ozen A, Karakoc-Aydiner E, Kiykim A, Schulz A, Steinmann S, Notarangelo LD, Gambineri E, Lionetti P, Shearer WT, Forbes LR, Martinez C, Moshous D, Blanche S, Fisher A, Ruemmele FM, Tissandier C, Ouachee-Chardin M, Rieux-Laucat F, Cavazzana M, Qasim W, Lucarelli B, Albert MH, Kobayashi I, Alonso L, Diaz De Heredia C, Kanegane H, Lawitschka A, Seo JJ, Gonzalez-Vicent M, Diaz MA, Goyal RK, Sauer MG, Yesilipek A, Kim M, Yilmaz-Demirdag Y, Bhatia M, Khlevner J, Richmond Padilla EJ, Martino S, Montin D, Neth O, Molinos-Quintana A, Valverde-Fernandez J, Broides A, Pinsk V, Ballauf A, Haerynck F, Bordon V, Dhooge C, Garcia-Lloret ML, Bredius RG, Kalwak K, Haddad E, Seidel MG, Duckers G, Pai SY, Dvorak CC, Ehl S, Locatelli F, Goldman F, Gennery AR, Cowan MJ, Roncarolo MG, Bacchetta R; Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT). Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. 2018 Mar;141(3):1036-1049.e5. doi: 10.1016/j.jaci.2017.10.041. Epub 2017 Dec 11.
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• Cornetta K, Duffy L, Turtle CJ, Jensen M, Forman S, Binder-Scholl G, Fry T, Chew A, Maloney DG, June CH. Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products. Mol Ther. 2018 Jan 3;26(1):280-288. doi: 10.1016/j.ymthe.2017.09.008. Epub 2017 Sep 12.
• 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.
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• Passerini L, Rossi Mel E, Sartirana C, Fousteri G, Bondanza A, Naldini L, Roncarolo MG, Bacchetta R. CD4(+) T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013 Dec 11;5(215):215ra174. doi: 10.1126/scitranslmed.3007320.
• Passerini L, Barzaghi F, Curto R, Sartirana C, Barera G, Tucci F, Albarello L, Mariani A, Testoni PA, Bazzigaluppi E, Bosi E, Lampasona V, Neth O, Zama D, Hoenig M, Schulz A, Seidel MG, Rabbone I, Olek S, Roncarolo MG, Cicalese MP, Aiuti A, Bacchetta R. Treatment with rapamycin can restore regulatory T-cell function in IPEX patients. J Allergy Clin Immunol. 2020 Apr;145(4):1262-1271.e13. doi: 10.1016/j.jaci.2019.11.043. Epub 2019 Dec 23.
• Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995 Aug 1;155(3):1151-64.
• Sato Y, Passerini L, Piening BD, Uyeda MJ, Goodwin M, Gregori S, Snyder MP, Bertaina A, Roncarolo MG, Bacchetta R. Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo. Clin Transl Immunology. 2020 Nov 25;9(11):e1214. doi: 10.1002/cti2.1214. eCollection 2020.
• Baecher-Allan CM, Hafler DA. The purification and functional analysis of human CD4+CD25high regulatory T cells. Curr Protoc Immunol. 2006 May;Chapter 7:7.4B.1-7.4B.12. doi: 10.1002/0471142735.im0704bs72.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2022
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2037

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: February 4, 2022
• First Posted (Actual): February 15, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2025
• Last Update Submitted That Met QC Criteria: May 19, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Gene therapy; autoimmunity; Regulatory T cells; FOXP3; Treg cells; Immune Dysregulation Polyendocrinopathy Enteropathy X-linked; Lentiviral; CD271; NGFR; immune suppression
• Other Study ID Numbers: IRB-63373; DRU-2020-7764 (Other Identifier: FDA Office of Orphan Products Development); RPD-2020-470 (Other Identifier: FDA Office of Orphan Products Development); 1R01FD007540-01 (U.S. FDA Grant/Contract); CLIN2-13259 (Other Grant/Funding Number: California Institute of Regenerative Medicine (CIRM))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No