Autologous Polyclonal Tregs for Lupus

Study Overview
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Brief Summary
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The primary purpose of this Phase 1 study is to evaluate the safety, tolerability, and effect of 3 different doses of Treg therapy in adults with skin (cutaneous) involvement of their lupus. Targeting cutaneous disease offers the ability to control background therapy, readily detect clinical effects, and perform research analyses not only in blood but also skin. Safety, disease activity, and mechanism of Tregs will be evaluated. The intent is to support dose selection for a future larger efficacy trial in lupus.

Detailed Description
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The investigational therapy in this trial, regulatory T cells (Tregs), is evaluating an alternative to traditional immunosuppressive therapies for the treatment of systemic lupus erythematosus (SLE, lupus). Too frequently, aggressive therapies are inadequate in the control of the disease and have potent side effects and complications. The collection and expansion of one's own T cells harnesses a naturally occurring regulatory mechanism to restore self-tolerance in people with lupus. Tregs are a specialized subset of T cells that function to control the immune response. Studies have shown that in active lupus, the numbers and function of Treg cells are significantly decreased, which contributes to an overactive immune system and an increase in disease activity. The hope is that these naturally occurring Treg cells can be used for the treatment of autoimmune diseases, including lupus.

Official Title
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A Phase I, Open-Label, Dose Escalation Trial Exploring the Safety and Tolerability of Autologous Polyclonal Regulatory T Cell Therapy in Adults With Active Cutaneous Lupus (ALE08)

Conditions
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Lupus Erythematosus, Cutaneous, Lupus Erythematosus, Discoid, Lupus Erythematosus, Systemic

Intervention / Treatment
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* Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent. Diagnosis of SLE by American College of Rheumatology (ACR) criteria or biopsy proven primary cutaneous lupus. Presence of ≥ 2 active cutaneous lupus lesions based on (1) visual morphology and (2) at least a grade 2 erythema on CLASI activity score. Histopathologic confirmation is required unless the active lesions are of the same morphology to previously histologically proven cutaneous lupus lesions. The cutaneous lupus lesions must include any of the following subtypes: Acute cutaneous lupus including maculopapular lupus rash and photosensitive lupus rash, Subacute cutaneous lupus, Chronic cutaneous lupus including discoid lupus and hypertrophic (verrucous) lupus, Lupus timidus Positive test for Epstein-Barr virus (EBV) antibody. Adequate venous access to support draw of 400 mL whole blood and infusion of investigational therapy. Exclusion Criteria: New onset of cutaneous lupus which has not been treated with broad spectrum sunscreen (UVA and UVB) in combination with either antimalarials or another systemic medication for at least 3 months. Prednisone dose > 15mg/day within the 30 days prior to screening. Addition of a new medication, or change in the dose of any background medication, used to treat any aspect of SLE. Specifically: addition or change in systemic glucocorticoids, antimalarials, methotrexate, mycophenolate mofetil, mycophenolic acid, azathioprine, cyclosporine, tacrolimus, thalidomide, lenalidomide, dapsone, acitretin, or isotretinoin within 90 days prior to screening treatment with cyclophosphamide within 90 days prior to screening. Doses of background medications at Screening visit: hydroxychloroquine > 400 mg/day, chloroquine > 250 mg/day, quinacrine >100 mg/day, methotrexate > 25 mg/week, mycophenolate mofetil (MMF)> 3000 mg/day, mycophenolic acid > 720 mg/day BID, azathioprine > 200 mg/day, cyclosporine > 5 mg/day divided BID, tacrolimus > 6 mg/day thalidomide > 300 mg/day, lenalidomide > 10 mg/day, dapsone > 250 mg/day, acitretin > 50 mg/d (or > 1 mg/kg/day), isotretinoin > 120 mg/d (or > 2 mg/kg/day). Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the 90 days prior to screening. Use of rituximab within the 12 months prior to screening. Change in dosing frequency, concentration, or applied surface area of topical steroids, tacrolimus, and/or pimecrolimus within 4 weeks prior to screening. Active severe central nervous system lupus. SELENA-SLEDAI's seizure, psychosis, organic brain syndrome, visual disturbance,cranial nerve disorder, lupus headache, cerebrovascular accident (CVA), vasculitis,arthritis, myositis, mucosal ulcers, pleurisy, pericarditis, and fever scores > 8 total. Active lupus nephritis (spot protein / creatinine ratio > 1.0 mg/mg). End stage renal disease (estimated glomerular filtration rate [eGFR] < 20 ml/min/1.73m^2 using the CKD-EPI equation [53]). Drug induced lupus. Hemoglobin < 10 g/dL. White blood cell (WBC) count < 2,500/ mm^3 (equivalent to < 2.5 x10^9/L). Lymphocyte count < 625/mm^3 (equivalent to < 0.625 x10^9/L). Absolute neutrophil count < 1,500/mm3 (equivalent to < 1.5 x10^9/L). Platelets < 75,000/mm^3 (equivalent to < 75 x 10^9/L). Liver function test (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase [ALK]) results that are ≥ 2 times the upper limit of normal (ULN). Direct bilirubin > ULN. Active bacterial, viral, fungal, or opportunistic infections requiring systemic antiinfective therapy. Presence of positive purified protein derivative tuberculin skin test (PPD, > 5mm induration [regardless of Bacille Calmette Guerin (BCG) vaccine administration]) or positive or indeterminate QuantiFERON(R)-TB Gold In-Tube Test (QFT-G_IT) at screening. Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C. Detectable circulating EBV or cytomegalovirus (CMV) genomes or active infection. Chronic infection that is currently being treated with suppressive anti-infective therapy, including but not limited to tuberculosis, pneumocystis, CMV, herpes zoster, and atypical mycobacteria. Herpes simplex virus infection requiring chronic, suppressive therapy with an anti-viral medication. Receipt of a live-attenuated vaccine within 12 months prior to screening. Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Pregnancy. Breastfeeding. Unwilling or unable to use reliable method(s) of contraception from four weeks prior to Day 0 throughout three months after Treg dosing (males) or for two years after Treg dosing (females). Note: investigators of female participants of childbearing potential on concurrent MMF, and those participants themselves, whether or not they plan to become pregnant, are strongly encouraged to participate in Mycophenolate Risk Evaluation and Mitigation Strategy (REMS). Use of an experimental therapeutic agent within the calendar year prior to screening. Use of biologic medications other than rituximab within the 90 days or 5 half-lives,whichever is greater, prior to screening. Concomitant medical condition that places the subject at risk by participating in this study, including but not limited to: another severe, systemic autoimmune disease or condition (besides lupus) requiring systemic immunosuppressive therapy (e.g., rheumatoid arthritis, systemic sclerosis, primary Sjogren's syndrome, primary vasculitis, psoriasis, multiple sclerosis, ankylosing spondylitis, and inflammatory bowel disease), or severe, progressive, or poorly controlled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease, either related or unrelated to SLE, or history of significant infection or recurrent infection that, in the investigator's opinion, places the subject at risk by participating in this study any other concomitant medical condition that, in the investigator's opinion, places the subject at risk by participating in this study. Comorbidities requiring glucocorticoid therapy, including those which have required three or more courses of systemic glucocorticoids within the previous 12 months. Current or history within the past year of substance abuse. Inability to comply with study and follow-up procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Treg Cohort<br>3-6 participants will receive a single infusion of 1 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded) | Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells<br> <br> * Other names: Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells;|
| Experimental: Medium Dose Treg Cohort<br>Sequential dose escalation, 3-6 subjects will receive a single infusion of 4 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded) | Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells<br> <br> * Other names: Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells;|
| Experimental: High Dose Treg Cohort<br>Sequential dose escalation, 3-6 participants will receive a single infusion of 16 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded) | Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells<br> <br> * Other names: Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Significant Adverse Events (AEs) Through Week 48 | A significant adverse event is any related National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 Grade 3 or higher AE or any related serious adverse event. Related is defined as being possibly, probably, or definitely related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee. | From time of signed informed consent to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Significant Adverse Events (AEs) Through Week 152 | A significant adverse event is any related National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 Grade 3 or higher AE or any related serious adverse event. Related is defined as being possibly, probably, or definitely related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee. | From time of signed informed consent to Week 152 | 
| Number of Grade 3 or Higher Adverse Events (AEs) Through Week 152 | Adverse events (AEs) Grade 3 or higher were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0. | From time of signed informed consent to Week 152 | 
| Number of Infection-Related Adverse Events (AEs) Through Week 152 | If the adverse event was believed to be caused by a viral, bacterial, or fungal organism, regardless of whether it was treated with antibiotics or not, then it was classified as infection-related. | From time of signed informed consent to Week 152 | 
| Number of Lupus Flares Through Week 152 by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Criteria | An activity score increase of ≥4 CLASI points defines a flare. A mild/moderate flare includes at least one of the following SELENA-SLEDAI criteria: Increase in the SLEDAI Score of ≥3 points, new or worse discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus, nasopharyngeal ulcers, pleuritic, pericarditis, arthritis, fever attributable to SLE; increase in prednisone (<0.5 mg/kg/day); added NSAID or Plaquenil; increase in PhGA (<2.5 [on a 3.0 indexed VAS scale]). A severe flare includes at least one of the following SELENA-SLEDAI criteria: Increase of >12 in the SLEDAI Score; new or worse CNS-SLE, vasculitis, nephritis, myositis, platelet count <60,000/mm^3, hemolytic anemia with hemoglobin <7% or decrease in hemoglobin >3%; prednisone >0.5 mg/kg/day; new Cyclophosphamide, Azathioprine, Methotrexate, Mycophenolate Mofetil, or hospitalization attributable to SLE; increase in PhGA to >2.5. | From time of signed informed consent to Week 152 | 
| Number Infusion-Related Adverse Events (AEs) Within 24 Hours of Infusion | Any infusion-related adverse events Grade 1 or higher within 24 hours of polyclonal Treg infusion. This study graded the severity of adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0. | From time of infusion to 24 hours post infusion | 
| Change From Baseline: Alkaline Phosphatase (ALK), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values are based on subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in g/dL: Albumin, Hemoglobin | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in mg/dL: Total Bilirubin, Creatinine | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in mmol/L: Potassium, Sodium, Chloride | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in Cell Counts: White Blood Cells (WBC), Total Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline Red Blood Cell Count | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in mm/hr: Sedimentation Rate (ESR) | Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. | Baseline (Visit 0) and Weeks 4, 12, 48, and 152 | 
| Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a validated, physician-based assessment tool used to measure cutaneous lupus severity. Severity is calculated based on disease activity (erythema and scale) and damage (dyspigmentation and scarring) for the cumulative areas of involved skin. Severity categories based on the CLASI activity score are as follows: mild (0-9), moderate (10-20), and severe (21-70). A 4-point or 20% change in the CLASI activity score identifies a clinically meaningful change. A 4-point increase in the CLASI activity score indicates a flare. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in SELENA-SLEDAI Total Score | The Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus (SLE) Disease Activity Index (SELENA-SLEDAI) score is a weighted scale score ranging from 0 to 105 based on the presence or absence of 24 manifestations of SLE. The SELENA-SLEDAI assesses disease activity for 10 days prior to and including the day of assessment. Positive change in the SELENA-SLEDAI score indicates increased disease activity. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in Patient's Global Assessment (PGA) | The global assessment (PGA) is a visual 3-inch analog scale from 0 to 3 in which the participant marks the scale according to perceived disease activity. A score of 0 corresponds to no lupus disease activity and a score of 3 corresponds to severe disease activity. A positive change from baseline indicates more disease activity. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in Physician's Global Assessment (PhGA) | The physician's global assessment (PhGA) is a visual analog 3-inch scale in the SELENA-SLEDAI that is scored from 0 to 3 by the physician. A score of 0 corresponds to no lupus disease activity and a score of 3 corresponds to severe disease activity. A positive change from baseline indicates more disease activity. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in Anti-dsDNA Antibody Titers | Double-stranded DNA is one of multiple diagnostic tests for SLE and high levels may be associated with disease activity. The positive range is based on the normal range from the local laboratory. A positive change from baseline value indicates the detection of autoantibodies to double-stranded DNA. | Baseline ( Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in Serum C3 Complement Levels | C3 is a blood test that measures the activity of the complement component 3 (C3) protein. The normal C3 range is 71 to 159 mg/dL. Those with active systemic lupus erythematosus (SLE) may have a lower-than-normal level of C3. A decrease in C3 level over time may indicate SLE disease activity. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 
| Change From Baseline in Serum C4 Complement Levels | C4 is a blood test that measures the activity of the complement component 4 (C4) protein. The normal range is 13 to 30 mg/dL. Individuals with active systemic lupus erythematosus (SLE) may have a lower-than-normal level of C4. A decrease in C4 level over time may indicate disease activity. | Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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active cutaneous lupus, systemic lupus erythematosus (SLE), autologous polyclonal regulatory T cell Therapy, polyclonal Tregs for treatment of lupus