Autologous Polyclonal Tregs for Lupus
Condition: Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic
MeSH terms: Lupus Erythematosus, Systemic; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid
Intervention: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: active cutaneous lupus; systemic lupus erythematosus (SLE); autologous polyclonal regulatory T cell Therapy; polyclonal Tregs for treatment of lupus

Summary:

      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.
    

Eligibility criteria:

        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.