Polyclonal Regulatory T Cells (PolyTregs) for Pemphigus
Condition: Pemphigus Foliaceus; Pemphigus Vulgaris
MeSH terms: Pemphigus
Intervention: Cohort 1: 1.0 x 10^8 PolyTregs; Cohort 2: 2.5x10^8 PolyTregs
Intervention description: Each participant will receive a target cell dose of 1.0 x 10^8 polyclonal Tregs.; Each participant will receive a target cell dose of 2.5x10^8 polyclonal Tregs.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: autologous polyclonal regulatory T cell therapy; PolyTregs; open-label; Phase 1 (safety)

Summary:

      T cells, a type of white blood cell called a lymphocyte, play an important role in the immune
      system. One subtype, the regulatory T cell (Treg) helps to regulate the immune system and may
      provide protection against the development of autoimmune disease. The hope is that these
      naturally occurring Treg cells can be utilized for the treatment of autoimmune disease and
      potentially replace the use of chronic immunosuppressive therapies that are associated with
      multiple side effects. There has been a small study showing safe administration of Tregs with
      decreased disease activity in patients with insulin-dependent diabetes. Tregs are being
      studied in lupus, cancer and organ transplantation.

      This phase I trial will be conducted as an open-label, dose-escalation, multicenter trial in
      adult participants with active pemphigus.The purpose of this study is to test the safety and
      effect of Treg therapy in participants who have skin (cutaneous) involvement due to
      pemphigus.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Ability to provide informed consent;

          -  Diagnosis of Pemphigus Vulgaris (PV) or Pemphigus Foliaceus (PF), defined by H&E
             staining (e.g., Haemotoxylin and Eosin) and direct immunofluorescence staining of skin
             biopsy at any time prior to enrollment;

          -  Pemphigus treated with systemic corticosteroids within the 2 years prior to screening
             (historic or current), or treated with rituximab ≥ 12 months prior to screening;

          -  Presence of:

               -  anti-Dsg3 antibodies (>20.0 U/ml) at screening visit consistent with diagnosis of
                  pemphigus vulgaris or,

               -  anti-Dsg1 antibodies (>20.0 U/ml) at screening visit consistent with diagnosis of
                  pemphigus foliaceus.

          -  Active of PV or PF as defined by Pemphigus Disease Area Index (PDAI) overall activity
             score 3-10 at screening visit, and PDAI overall activity score 1-12 at baseline visit;

          -  Positive test for Epstein-Barr Virus (EBV) antibody;

          -  Adequate venous access to support draw of 400 ml whole blood and infusion of
             investigational therapy; and

          -  An absolute Treg count of ≥ 42 cells/μL within 6 weeks prior to whole blood collection
             at Week -2 (i.e., 2 weeks prior to planned PolyTreg Infusion).

        Exclusion Criteria:

          -  Initiation of systemic corticosteroid therapy, prednisone dose > 25 mg/d (or
             equivalent) or change in prednisone dose within 4 weeks prior to screening;

          -  Addition of a new medication, or change in the dose of any background medication used
             to treat any aspect of pemphigus within the timeframes listed below. Specifically:

               -  methotrexate, mycophenolate mofetil, mycophenolic acid, azathioprine,
                  cyclosporine or dapsone within the 6 weeks prior to screening or in the time
                  between screening and study drug infusion,

               -  intravenous Immunoglobulin (IVIG) within 12 weeks prior to screening or in the
                  time between screening and study drug infusion (subjects on IVIG must be on
                  stable dose for at least 12 weeks prior to screening),

               -  treatment with cyclophosphamide within 12 weeks prior to screening or in the time
                  between screening and study drug infusion.

          -  Doses of background medications at screening:

               -  methotrexate > 25 mg/week,

               -  mycophenolate mofetil > 3000 mg/d,

               -  mycophenolic acid > 1080 mg/bid,

               -  azathioprine > 200 mg/d,

               -  cyclosporine > 2 mg/kg/d,

               -  dapsone >250 mg/d,or

               -  intravenous immunoglobulin (IVIG) > 4mg/kg monthly.

          -  Use of rituximab within the 12 months prior to screening;

          -  Change in dosing frequency, concentration, or applied surface area of topical steroids
             and/or topical calcineurin inhibitors within 2 weeks prior to screening;

          -  Paraneoplastic pemphigus;

          -  Pemphigus erythematosus;

          -  Pemphigus vegetans;

          -  Immunoglobulin A (IgA) pemphigus;

          -  Drug-induced pemphigus;

          -  Blood donation within 10 weeks prior to baseline visit (Day 0);

          -  Hemoglobin < 10 g/dL;

          -  White blood cell (WBC) count < 3,000/ mm^3 (equivalent to < 3 x10^9/L);

          -  Lymphocyte count < 800/mm^3 (equivalent to < 0.8 x10^9/L);

          -  Absolute neutrophil count < 1,500/mm^3 (equivalent to < 1.5 x10^9/L);

          -  Platelets < 100,000/mm^3 (equivalent to < 100 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;

          -  End stage renal disease [estimated glomerular filtration rate (eGFR) < 20
             ml/min/1.73m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
             equation];

          -  At or within three months of screening:

               -  a positive QuantiFERON(R)-TB Gold test or positive purified protein derivative
                  tuberculin skin test (PPD) [>5mm induration, regardless of Bacille Calmette
                  Guerin (BCG) vaccine administration] unless completion of treatment has been
                  documented for active Tuberculosis (TB),

               -  an indeterminate QuantiFERON (R)-TB Gold test unless followed by a subsequent
                  negative PPD or negative QuantiFERON(R)-TB Gold test as well as a consultation
                  with and clearance by local infectious disease (ID) department.

          -  Recent or ongoing active bacterial, viral, fungal, or opportunistic infections
             requiring systemic anti-infective therapy;

          -  Evidence of current or prior infection with human immunodeficiency virus (HIV),
             hepatitis B [as assessed by HBsAg and anti-hepatitis B core antigen (HBc) Ab] or
             hepatitis C [as assessed by anti-Hepatitis C Virus (anti-HCV) Ab];

          -  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, with the exception of historical orolabial or localized
             cutaneous herpes simplex infections treated with suppressive anti- viral therapy;

          -  Receipt of a live-attenuated vaccine within 12 months prior to screening;

          -  Concomitant malignancies or a history of malignancy, with the exception of completely
             treated basal cell carcinoma of the skin;

          -  Pregnancy;

          -  Lactating or breastfeeding;

          -  Unwilling or unable to use reliable method(s) of contraception:

               -  For females of child-bearing potential, from four weeks prior to Day 0 through

                  1 year after Treg dosing;

               -  For males, from the day of Treg infusion (baseline visit) to three months after
                  Treg infusion.

          -  Use of an investigational therapeutic medication, or other biologic medications except
             rituximab, within the past 90 days, or 5 half-lives prior to screening, whichever is
             greater;

          -  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 pemphigus)
                  requiring systemic immunosuppressive therapy (e.g., rheumatoid arthritis,
                  Systemic Lupus Erythematosus (SLE), 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, or

               -  history of significant infection or recurrent infection that, in the
                  investigator's opinion, places the subject at risk by participating in this
                  study, or

               -  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; or

          -  Inability to comply with study and follow-up procedures.