Polyclonal Regulatory T Cells (PolyTregs) for Pemphigus

A Phase I, Open-Label, Multicenter Trial Exploring the Safety and Tolerability of Autologous Polyclonal Regulatory T Cell Therapy in Adults With Active Pemphigus (APG01)

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.

Study Overview

• Status: Terminated
• Conditions: Pemphigus Vulgaris; Pemphigus Foliaceus
• Intervention / Treatment: Biological: Cohort 1: 1.0 x 10^8 PolyTregs; Biological: Cohort 2: 2.5x10^8 PolyTregs

Detailed Description

Up to 12 adults between the ages of 18 and 75 years of age who have been diagnosed with pemphigus and meet all other entry criteria will be enrolled to receive one infusion of their own expanded Tregs at one of the following doses:

• 1.0 x 10^8 PolyTregs or
• 2.5 x 10^8 PolyTregs.

Safety, disease activity, and mechanism of action will be assessed over a three year period, using biospecimens from blood and skin. Study therapy administration will occur during an overnight stay, followed by 2 weekly visits, then monthly visits from Week 8 to Week 12, then quarterly visits from Week 26 to Week 52, then twice a year visits until Week 156.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • University of California San Francisco School of Medicine: Department of Dermatology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Health Care: Department of Dermatology
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center: Department of Dermatology
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center: Department of Dermatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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 1: 1.0 x 10^8 PolyTregs; A single intravenous infusion of 1.0 x 10^8 PolyTregs will be administered.	Biological: Cohort 1: 1.0 x 10^8 PolyTregs; Each participant will receive a target cell dose of 1.0 x 10^8 polyclonal Tregs.; Other Names: Polyclonal Regulatory T Cells; autologous PolyTregs; CD4+CD127lo/negCD25+ PolyTregs
Experimental: Cohort 2: 2.5x10^8 PolyTregs; A single intravenous infusion of 2.5x10^8 PolyTregs will be administered.	Biological: Cohort 2: 2.5x10^8 PolyTregs; Each participant will receive a target cell dose of 2.5x10^8 polyclonal Tregs.; Other Names: Polyclonal Regulatory T Cells; autologous PolyTregs; CD4+CD127lo/negCD25+ PolyTregs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Significant Adverse Events Through Week 52	Number of significant adverse events, defined as any related National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher adverse event or any related serious adverse event (SAE). Related is defined as being possibly related or related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee. An SAE is any untoward medical occurrence that, at any dose* results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells.	Up to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Significant Adverse Events	Number of significant adverse events, defined as any related National Cancer Institute's (NCI's) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher adverse event or any related serious adverse event. Related is defined as being possibly related or related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee.	From the start of investigational product infusion through Week 156.
Number of All Adverse Events	An adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom, or disease, temporally associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research.	From the start of investigational product infusion through Week 156.
Number of All NCI-CTCAE Grade 3 or Higher Adverse Events	Adverse events Grade 3 or higher were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0.	From the start of investigational product infusion through Week 52.
Number of All NCI-CTCAE Grade 3 or Higher Adverse Events	Adverse events Grade 3 or higher were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0.	From the start of investigational product infusion through Week 156.
Number of All SAEs	Number of all serious adverse events, defined as adverse events that result in the following outcomes (21 CFR 312.32(a) and ICH E2A): 1. Death 2. A life-threatening event: An AE or SAR is considered "life-threatening" if, in the view of either the investigator or DAIT, NIAID, its occurrence places the subject at immediate risk of death. It does not include an AE or SAR that, had it occurred in a more severe form, might have caused death. 3. Inpatient hospitalization or prolongation of existing hospitalization 4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5. Congenital anomaly or birth defect 6. Important medical event that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above.	From the start of investigational product infusion through Week 156.
Number of All Infection Related Events	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 the start of investigational product infusion through Week 156.
Number of All Infusion Reactions	Defined as any adverse reaction of National Cancer Institute - Common Terminology Criteria Grade 1 and higher occurring within 24 hours of infusion. An adverse reaction means any AE caused by a drug.	Within 24 hours of infusion
Change in Pemphigus Disease Area Index (PDAI) Score From Baseline	The PDAI consists of a total activity score and a total damage score. The total activity score is a sum of the activity scores for skin, scalp and mucous membrane. The total activity score can range from 0 to 250. The total damage score is a sum of damage scores for skin and scalp. The total damage score can range from 0 to 13. Higher scores represent higher disease activity.	Weeks 1, 2, 8, 12, 26, 39, 52, 78, 104, 130, and 156
Change in Desmoglein 1 and 3 Titers by ELISA From Baseline	Autoantibodies were measured by Enzyme-Linked Immunosorbent Assays (ELISA). Blood samples were taken from participants at baseline and Weeks 1, 2, 8, 12, 26, 39, 52, 78, 104, 130, and 156. If the desmoglein 1 or desmoglein 3 titer was below the limit of detection, the lower limit of detection at the central lab was imputed. The lower limit of detection for both desmoglein 1 and desmoglein 3 was 2.5 U/mL. Change was calculated as the post-baseline value minus the baseline value. A positive difference reflects an increase in the desmoglein titer value over time; a negative difference reflects a decreased desmoglein titer over time.	Weeks 1, 2, 8, 12, 26, 39, 52, 78, 104, 130, and 156
Number of Participants Experiencing a Relapse/Flare	Pemphigus relapses/flares were assessed using the consensus definition of 3 or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a patient who has achieved disease control.	From the start of investigational product infusion through Week 156.
Time to Relapse (Flare)	Pemphigus relapses/flares will be assessed using the consensus definition of 3 or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a patient who has achieved disease control. Time to flare is defined as the number of days between the date of the flare and the date of the investigational product infusion. Only participants who experienced a flare are summarized.	From the start of investigational product infusion through Week 156.
Number of Participants on Prednisone Dose ≤10 mg/Day	Defined as the number of participants who were taking 0 mg/day, >0 and <=10 mg/day, or >10 mg/day of prednisone at the time of the associated study visit.	Weeks 12, 26, 39, 52, 78, 104, 130, and 156

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Rho Federal Systems Division, Inc.; Autoimmunity Centers of Excellence
• Investigators: Study Chair: David Wofsy, M.D., University of California San Francisco School of Medicine: Lupus Clinic and Rheumatology Clinical Research Center; Study Chair: Haley Naik, MD,MHSc, University of California San Francisco School of Medicine: Department of Dermatology; Study Chair: Anna Haemel, MD, University of California San Francisco School of Medicine: Department of Dermatology; Study Chair: Michael Rosenblum, MD, Ph.D., University of California San Francisco School of Medicine: Department of Dermatology; Study Chair: Jeffrey Bluestone, Ph.D., UCSF School of Medicine: UCSF Diabetes Clinic

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Autoimmunity Centers of Excellence (ACE) website

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2017
• Primary Completion (Actual): December 10, 2020
• Study Completion (Actual): January 9, 2023

Study Registration Dates

• First Submitted: August 2, 2017
• First Submitted That Met QC Criteria: August 2, 2017
• First Posted (Actual): August 4, 2017

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: open-label; autologous polyclonal regulatory T cell therapy; PolyTregs; Phase 1 (safety)
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Autoimmune Diseases; Skin Diseases, Vesiculobullous; Pemphigus
• Other Study ID Numbers: DAIT APG01; APG01 (Other Identifier: Autoimmunity Centers of Excellence (ACE)); NIAID CRMS ID#: 37534 (Other Identifier: DAIT NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No