Pemphigus Vulgaris
Conditions
Brief summary
This is an investigator-initiated, single-center, single-arm, open-label exploratory clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of autologous CD19 CAR-T cell therapy in patients with refractory pemphigus vulgaris.
Detailed description
This is an investigator-initiated, open-label, single-center, single-arm exploratory interventional study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immune reconstitution, and preliminary clinical efficacy of autologous CD19 CAR-T cell therapy in adult patients with moderate-to-severe refractory pemphigus vulgaris. Eligible participants are adults with refractory pemphigus vulgaris. After enrollment, participants will undergo leukapheresis for ex vivo manufacturing of autologous CD19 CAR-T cells. After product release, participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 2 to 7 days prior to CAR-T infusion. Participants will receive a single intravenous infusion of autologous CD19 CAR-T cells at a protocol-defined dose (1 X 10\^6 CAR-positive T cells per kilogram of body weight). Premedication may be administered at investigator discretion. No comparator group is included. Participants will be followed for up to 96 weeks after infusion. Safety assessments include monitoring for cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, infections, cytopenias, organ toxicities, and other treatment-emergent adverse events. Efficacy assessments include changes in PDAI score, disease control, Physician Global Assessment (PGA), Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), relapse rate, time to relapse, and corticosteroid-sparing effects. Translational assessments include peripheral CD19-positive B-cell depletion and reconstitution, B-cell subset dynamics, serum anti-desmoglein 1 and 3 antibody levels, and serum cytokine profiles. CAR-T pharmacokinetics will be evaluated through CAR transgene copy number and circulating CAR-positive T-cell detection, including expansion and persistence metrics.
Interventions
BIOLOGICALAutologous CD19 CAR-T cells
Autologous CD19 CAR-T cells are manufactured ex vivo using the participant's own T cells collected by leukapheresis. The CAR construct targets CD19-expressing B cells and consists of a single-chain variable fragment directed against CD19. Participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide prior to CAR-T cell infusion according to the protocol-defined schedule. Following completion of lymphodepletion, each participant will receive a single intravenous infusion of autologous CD19 CAR-T cells under inpatient monitoring. Premedication, including acetaminophen and diphenhydramine, may be administered prior to infusion at the investigator's discretion in accordance with institutional practice.
Sponsors
Jinbo Chen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following criteria: 1. Ability to provide written informed consent. 2. Age 18 to 70 years at screening, male or female. 3. Diagnosis of pemphigus vulgaris confirmed by clinical presentation, histopathology, direct immunofluorescence (DIF), and positive anti-desmoglein 3 and/or anti-desmoglein 1 antibodies. 4. Moderate-to-severe disease activity defined as Pemphigus Disease Area Index (PDAI) ≥ 15 at screening. 5. Refractory pemphigus vulgaris is defined as inadequate response, disease relapse, or treatment dependence following systemic corticosteroids and rituximab-based therapy for at least 6 months, with persistent disease activity meeting at least one of the following criteria: 1. Ongoing active disease with the appearance of new erythema, blisters, or erosions; 2. Persistently elevated anti-desmoglein 1 or anti-desmoglein 3 antibody titers \> 100 U/mL; 3. Inability to taper systemic corticosteroids to \< 20 mg/day prednisone equivalent (i.e., ≥ 4 tablets/day of standard prednisone dosing). 6. Requirement for systemic therapy at screening due to active disease. 7. Adequate vascular access for leukapheresis. 8. Life expectancy greater than 6 months. 9. Participants must have adequate organ function as defined below: 1. Hematologic function: absolute neutrophil count ≥ 1.0 × 10⁹/L, platelet count ≥ 50 × 10⁹/L, hemoglobin ≥ 80 g/L. 2. Renal function: Creatinine clearance ≥ 40 mL/min. 3. Hepatic function: ALT and AST ≤ 2.5 × upper limit of normal; total bilirubin ≤ 1.5 × upper limit of normal. 4. Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% with no clinically significant cardiac dysfunction. 5. Pulmonary function: Dyspnea ≤ Grade 1 (CTCAE v5.0) and oxygen saturation (SpO₂) ≥ 92% on room air. 6. Coagulation function: international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal, with no clinically significant coagulopathy. 9\. No evidence of clinically significant active infection at baseline evaluation. 10\. Reproductive Criteria: Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) test within 48 hours prior to initiation of lymphodepleting chemotherapy. Women of childbearing potential must agree to use effective contraception during study participation and for at least 12 months after CAR-T infusion. Male participants must agree to use effective contraception and avoid sperm donation during study participation and for at least 12 months after infusion.
Exclusion criteria
Participants meeting any of the following criteria will be excluded: 1. Active uncontrolled infection at screening, requiring systemic antimicrobial therapy. Participants with active tuberculosis, hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis infection will be excluded. Participants with hepatitis B surface antigen and/or hepatitis B core antibody positivity may be eligible only if HBV DNA is below the lower limit of quantification and appropriate antiviral prophylaxis is provided at the investigator's discretion. 2. History of other active autoimmune disease requiring systemic immunosuppression. 3. Previous treatment with any gene-modified cellular therapy, including CAR-T or CAR-NK therapy. 4. Prior allogeneic stem cell or solid organ transplantation. 5. Severe or uncontrolled cardiovascular, pulmonary, hepatic, or renal disease that would increase risk associated with lymphodepleting chemotherapy or CAR-T cell infusion. 6. Use of high-dose systemic corticosteroids (\>1 mg/kg/day prednisone equivalent) within 7 days prior to leukapheresis. 7. Use of rituximab or other B-cell-targeted biologics within protocol-defined washout period. 8. Use of intravenous immunoglobulin, plasma exchange, or other intensive immunomodulatory therapy within 2 weeks prior to leukapheresis. 9. Received live vaccine within 8 weeks prior to screening. 10. History of malignancy within 5 years prior to enrollment, except adequately treated non-melanoma skin cancer or in situ carcinoma. 11. Pregnancy or breastfeeding. 12. Known hypersensitivity to any component of lymphodepleting chemotherapy or CAR-T cell product. 13. Any condition that, in the investigator's judgment, would compromise patient safety or study integrity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Treatment-Emergent Adverse Events | From initiation of lymphodepleting chemotherapy through Day 90 after CAR-T cell infusion | Treatment-emergent adverse events, serious adverse events, dose-limiting toxicities, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, infections, cytopenias, organ toxicities, infusion-related reactions, and clinically significant laboratory abnormalities will be assessed. Adverse events will be graded according to CTCAE v5.0, and immune effector cell-related toxicities will be assessed according to applicable consensus grading criteria. |
| Change From Baseline in PDAI Score at Week 12 | Baseline and Week 12 | The change from baseline in Pemphigus Disease Area Index (PDAI) score at Week 12 will be assessed to evaluate preliminary clinical efficacy of autologous CD19 CAR-T cell therapy in patients with refractory pemphigus vulgaris. |
| Proportion of participants achieving disease control at Week 4 after CAR-T infusion | Week 4 | Disease control is defined as cessation of new active cutaneous or mucosal lesions with established lesion healing or no further progression of existing lesions, as assessed by the investigator. This endpoint evaluates the early clinical response following CD19 CAR-T cell therapy and reflects initial disease stabilization after B-cell depletion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Rate Through Week 96 | From disease control through Week 96 after CAR-T cell infusion | Relapse rate will be assessed as the proportion of participants who experience relapse after achieving disease control. Relapse is defined as the occurrence of three or more new lesions within one month that do not heal spontaneously within one week, or extension of established lesions. |
| Time to First Relapse | From disease control through Week 96 after CAR-T cell infusion | Time to first relapse will be assessed as the time from achievement of disease control to the first documented relapse. |
| Change From Baseline in Daily Prednisone-Equivalent Corticosteroid Dose | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in daily systemic corticosteroid use will be assessed using prednisone-equivalent dose in milligrams per day at scheduled follow-up visits. A lower prednisone-equivalent daily dose indicates reduced corticosteroid requirement after CAR-T cell therapy. |
| Incidence of Serious Adverse Events and Long-Term Safety Events | From informed consent through Week 96 after CAR-T cell infusion | Serious adverse events, infections, prolonged cytopenias, organ dysfunction, secondary malignancies, and other clinically significant long-term safety events will be recorded throughout the study follow-up period. |
| Change From Baseline in Pemphigus Disease Area Index （PDAI） Score Over Time (Range 0-263) | Baseline through Week 96 after CAR-T cell infusion | Changes from baseline in Pemphigus Disease Area Index (PDAI) score will be assessed at scheduled follow-up visits to evaluate the durability of clinical response. The total PDAI score ranges from 0 to 263, with higher scores indicating more severe disease. |
| Change From Baseline in Physician Global Assessment Score (PGA) (Range 0-10) | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in PGA score will be assessed at scheduled follow-up visits. PGA is a physician-rated global assessment of pemphigus disease severity, with higher scores indicating more severe disease activity. |
| Change from Baseline in Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) (Range 0-206) | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in ABSIS will be assessed at scheduled follow-up visits. ABSIS is used to evaluate autoimmune bullous disease activity, with higher scores indicating more severe disease activity. |
| Proportion of participants achieving disease control at Week 12 | Week 12 | Disease control is defined as cessation of new active cutaneous or mucosal lesions with healing or stabilization of existing lesions, as assessed by the investigator. This endpoint evaluates the durability and consolidation of clinical response following CD19 CAR-T cell therapy in patients with refractory pemphigus vulgaris. |
| Change From Baseline in Anti-Desmoglein 1 and Anti-Desmoglein 3 Antibody Levels | Baseline through Week 96 after CAR-T cell infusion | Serum anti-desmoglein 1 and anti-desmoglein 3 antibody levels will be measured to evaluate changes in pemphigus-related autoantibody responses after CD19 CAR-T cell therapy. |
| Peripheral CD19-Positive B-Cell Depletion and Reconstitution | Baseline through Week 96 after CAR-T cell infusion | Peripheral CD19-positive B-cell counts and B-cell subset dynamics will be assessed to evaluate the pharmacodynamic effect of CD19 CAR-T cell therapy, including B-cell depletion, time to B-cell aplasia, duration of B-cell depletion, and B-cell reconstitution. |
| Number of Circulating CAR-Positive T Cells in Peripheral Blood | From CAR-T cell infusion through Week 96 | The number of circulating CAR-positive T cells in peripheral blood will be measured by flow cytometry at scheduled time points after CAR-T cell infusion to assess in vivo CAR-T cell expansion. |
| CAR Transgene Copy Number in Peripheral Blood | From CAR-T cell infusion through Week 96 | CAR transgene copy number in peripheral blood will be measured by quantitative polymerase chain reaction or digital PCR at scheduled time points after CAR-T cell infusion to assess CAR-T cell expansion and persistence. |
| Change From Baseline in Serum Cytokine Levels | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in serum cytokine levels will be measured to characterize immune activation after CAR-T cell infusion and to support evaluation of cytokine release syndrome. Cytokines include interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-10 (IL-10), and interleukin-17A (IL-17A). |
| Duration of Detectable CAR-T Cells in Peripheral Blood | From CAR-T cell infusion through Week 96 | The duration of detectable CAR-T cells in peripheral blood will be assessed based on the time from CAR-T cell infusion to the last time point at which CAR-positive T cells or CAR transgene copies remain detectable. |
| Change From Baseline in Lymphocyte Subset Counts | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in lymphocyte subset counts will be assessed at scheduled follow-up visits by flow cytometry to characterize immune reconstitution after CD19 CAR-T cell therapy. Lymphocyte subsets include CD3-positive T cells, CD4-positive T cells, CD8-positive T cells, CD19-positive B cells, and natural killer cells. |
| Change From Baseline in B-Cell Subset Counts | Baseline through Week 96 after CAR-T cell infusion | Change from baseline in B-cell subset counts will be assessed at scheduled follow-up visits by flow cytometry to characterize B-cell depletion and reconstitution after CD19 CAR-T cell therapy. B-cell subsets may include naïve B cells, non-switched memory B cells, switched memory B cells, and plasmablasts. |
Countries
China
Contacts
CONTACTJinbo Chen, MD, PhD
CONTACTXiaoya Du
Outcome results
None listed