Exploratory Clinical Study of Anti-BCMA-CD19 CAR-T Cell Therapy for Relapsed/Refractory IgG4-Related Disease
Phase: PHASE2
Conditions: IgG4 Related Disease, B-cell Mediated Autoimmune Disorders
Sponsor: Chinese PLA General Hospital

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 1 - 
 
 
Exploratory Study of Anti-BCMA–CD19 CAR-T Cell Therapy 
in Relapsed or Refractory IgG4-Related Disease 
 
 
Principal Investigator 
Professor JIAN ZHU 
Institution 
Department of Rheumatology & Immunology, First Medical 
Center, Chinese PLA General Hospital 
Address 
No. 28 Fuxing Road, Haidian District, Beijing 100853, China 
NCT 
 
Document Type 
Study Protocol 
Document Date 
Jul 15, 2025 
Version 
V1.0 
 
 
 
Confidentiality Statement 
This document contains confidential information intended solely for use in the conduct of the clinical 
trial. Unauthorized disclosure or reproduction of this document, in whole or in part, is prohibited 
without prior written permission from the sponsor. 
 
 
 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 1 - 
Sponsor 
The First Medical Center, Chinese PLAGH 
Principal InvesƟgator 
Jian Zhu, Professor 
CollaboraƟng InsƟtuƟon 
Cancer PrevenƟon and Treatment Research InsƟtute, Xuzhou 
Medical University 
CollaboraƟng InvesƟgator 
Min Shi, Professor 
Title 
Exploratory clinical study of anƟ-BCMA–CD19 CAR-T cell injecƟon 
for relapsed or refractory IgG4-related disease. 
Protocol Num. 
2025-07-15 
Planned Enrollment 
9 subjects 
ObjecƟves 
Primary objecƟve 
- 
To explore the eﬃcacy and safety of anƟ-BCMA–CD19 CAR-T 
cell injecƟon for the treatment of relapsed or refractory 
IgG4-related disease. 
Secondary objecƟves 
- 
To characterize the pharmacokineƟcs (PK) and 
pharmacodynamics (PD) of the anƟ-BCMA–CD19 CAR-T cell 
injecƟon. 
Exploratory objecƟve 
- 
To explore changes in the immune microenvironment of 
peripheral blood, bone marrow and lesions before and aŌer 
treatment with the anƟ-BCMA–CD19 CAR-T cell injecƟon. 
End points 
Primary end points 
- 
Safety end points 
♦ 
Dose-limiƟng toxicity (DLT): deﬁned as any grade 3 or 
higher toxicity related to CAR-T cells occurring within 28 
days aŌer infusion. The following are excluded: 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 2 - 
1. 
Grade 3 cytokine release syndrome (CRS) that 
responds to appropriate medical intervenƟon within 
3 days (recovering to grade 2 or lower). 
2. 
Grade 3/4 tumor lysis syndrome (TLS) lasƟng less than 
7 days. 
3. 
Hematologic toxic eﬀects: (i) any grade 3 neutropenia 
at any Ɵme or grade 4 neutropenia lasƟng less than 
14 days; (ii) any grade 3 anemia at any Ɵme or grade 4 
anemia lasƟng less than 14 days; (iii) any grade 3 
thrombocytopenia 
at 
any 
Ɵme 
or 
grade 4 
thrombocytopenia lasƟng less than 21 days; (iv) all 
other cytopenias except the neutropenia, anemia and 
thrombocytopenia listed above. 
4. 
Non-hematologic toxic eﬀects: (i) fever of any degree, 
including febrile neutropenia; (ii) grade 3 diarrhea 
lasƟng less than 72 hours; (iii) grade 3 nausea or 
vomiƟng lasƟng less than 72 hours; (iv) grade 3 
faƟgue lasƟng less than 7 days. 
5. 
Grade 3/4 elevaƟons of aminotransferases, bilirubin, 
creaƟne kinase, blood urea nitrogen or creaƟnine 
lasƟng less than 7 days; (vi) asymptomaƟc elevaƟon 
of lipase in the absence of any clinical signs or 
symptoms of pancreaƟƟs; (vii) any asymptomaƟc 
grade 3 non-hematologic laboratory abnormality that 
is rapidly reversible (returning to baseline or grade 2 
or lower within 7 days). 
♦ 
Adverse events, serious adverse events, laboratory 
abnormaliƟes and the grade and frequency of adverse 
events of special interest (including CRS and immune 
eﬀector cell–associated neurotoxicity syndrome [ICANS]). 
- 
Eﬃcacy end points 
♦ 
Primary eﬃcacy end-point measure:  
Change from baseline in the IgG4-related disease response 
index (IgG4-RD RI) at W12 and W26. 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 3 - 
♦ 
Secondary eﬃcacy end-point measures:  
1. 
Change from baseline in lesion size on imaging at 
W12 and W26. 
2. 
Change from baseline in IgG4 levels at W12 and W26. 
3. 
Change from baseline in IgE, IgG and absolute 
eosinophil count at W12 and W26. 
4. 
Change from baseline in histopathology of the lesion 
at W26 or at the Ɵme of peripheral blood B-cell 
recovery. 
Secondary end points 
- 
Ampliﬁcation and persistence of anti-BCMA–CD19 CAR-T cells 
in vivo: 
♦ 
Main PK parameters: peak expansion (Cmax), Ɵme to peak 
expansion (Tmax) and blood exposure. 
♦ 
Main PD parameters: changes in cytokines and levels of 
CD19+B cells. 
Exploratory end points 
- 
Changes in the relative abundance and functional status of key 
immune cell subsets and B-cell subsets (in peripheral blood, 
bone marrow and lesion tissue) and related cell-communication 
factors before and after treatment (baseline and W26). 
Study design 
This is a prospecƟve exploratory clinical trial in subjects with 
relapsed or refractory IgG4-related disease to explore the safety 
and 
eﬃcacy 
of 
anƟ-BCMA–CD19 
CAR-T cell 
injecƟon. 
Cyclophosphamide is a commonly used immunosuppressant for 
autoimmune diseases, and its adverse-event proﬁle (e.g., nausea) 
is well understood and generally accepted by paƟents. In cell 
therapy, cyclophosphamide is rouƟnely used as a lymphodepleƟon 
agent 
and 
is 
combined 
with 
ﬂudarabine 
to 
enhance 
lymphodepleƟon and reduce immune rejecƟon. Studies have 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 4 - 
shown that cyclophosphamide combined with ﬂudarabine 
lymphodepleƟon is well tolerated and eﬀecƟve in various immune 
diseases. Therefore, cyclophosphamide in combinaƟon with 
ﬂudarabine will be used in this study for lymphodepleƟon. 
The main study consists of a screening period (D−45 to D−21), an 
autologous CAR-T cell expansion period (D−20 to D−6), 
lymphodepleƟon chemotherapy and rest observaƟon (D−5 to D−1), 
and a cell-infusion and primary end-point assessment period (D0 to 
w26 aŌer infusion). AŌer the end of the main study, subjects may 
enter an extension observaƟon period (w27 to W52 aŌer infusion) 
if they wish. 
Screening period (D−45 to D−21) 
AŌer signing an informed-consent form, potenƟal subjects undergo 
screening procedures to determine eligibility according to inclusion 
and exclusion criteria. 
Autologous CAR-T cell expansion period (D−20 to D−6) 
AŌer leukapheresis at the First Medical Center of the Chinese 
PLAGH, peripheral blood mononuclear cells are transported by cold 
chain to the Cancer PrevenƟon and Treatment Research InsƟtute of 
Xuzhou Medical University to prepare the anƟ-BCMA–CD19 CAR-T 
cell product. The preparaƟon is expected to take 2 weeks. 
LymphodepleƟon chemotherapy (D-5 to D−3) 
The study uses a 3+3 dose-escalaƟon design and plans to enroll 9 
subjects. LymphodepleƟon chemotherapy begins 5 days before 
infusion. The regimen is as follows: 
(i) Cyclophosphamide: 250 mg/m2/d, i.v. × 3 days, (D−5 to D−3). 
(ii) Fludarabine: 30 mg/m2/d, i.v. × 3 days, (D−5 to D−3). 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 5 - 
For older paƟents, paƟents with low blood counts or poor 
performance status, or paƟents with abnormal renal funcƟon, the 
dose may be adjusted to reduce the ﬂudarabine dose by 20-50 
percent of the standard regimen; cyclophosphamide remains at 250 
mg/m2/d for 3 consecuƟve days (D−5 to D−3). InvesƟgators may 
adjust the dose and schedule at his or her discreƟon according to 
individual tolerance. Safety, pharmacokineƟcs and eﬃcacy will be 
assessed. 
Rest observaƟon (D-2 to D−1) 
ExaminaƟons and assessments will be conducted according to the 
study protocol. 
Cell infusion and primary end-point assessment (D0 to W26 aŌer 
infusion) 
AnƟ-BCMA–CD19 CAR-T cells will be infused intravenously 2 days 
aŌer compleƟon of lymphodepleƟon chemotherapy (D0). Eﬃcacy 
and safety evaluaƟons will be performed before infusion, during 
infusion and at mulƟple Ɵme points aŌerward (on the infusion day 
and on D3, D7, D10 and W2, 3, 4, 8, 12, 16, 20 and 26 aŌer infusion). 
Eﬃcacy evaluaƟons will be conducted at W2, 4, 8, 12, 16, 20 and 26 
aŌer infusion. AddiƟonal assessments may be performed at the 
invesƟgator’s discreƟon. 
Safety evaluaƟons will include follow-up through W26 aŌer 
infusion. 
Extension observaƟon period (W27 to W52 aŌer infusion) 
During this period, eﬃcacy and safety are evaluated. Eﬃcacy 
assessments will be conducted at W38 and W52 aŌer infusion. 
AddiƟonal assessments may be performed at the invesƟgator’s 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 6 - 
discreƟon. Subjects will be followed for safety through W26 aŌer 
infusion. 
Dose escalaƟon 
Previous clinical studies of anƟ-BCMA–CD19 CAR-T cell injecƟon 
(ChiCTR2200061267 and ChiCTR2000033567) showed controllable 
low-grade CRS and no other serious adverse events. This study will 
conƟnue to use the 3+3 dose-escalaƟon method. 
Three dose cohorts will be evaluated, each with 3 subjects and 
allowing a 20% variaƟon in total infused cells: 
1. 
Low-dose cohort: 1×10^6 CAR-T cells/kg. 
2. 
Intermediate-dose cohort: 2×10^6 CAR-T cells/kg. 
3. 
High-dose cohort: 3×10^6 CAR-T cells/kg. 
LymphodepleƟon 
chemotherapy 
Subjects must be assessed by the invesƟgator as suitable for 
lymphodepleƟon; there must be no uncontrolled acƟve infecƟon 
before chemotherapy, and body temperature must not exceed 38°C 
within 48 hours before dosing. 
During D-5 to D-3 before infusion, subjects will receive the 
prescribed chemotherapy regimen. InvesƟgators may adjust the 
dose and schedule according to individual tolerance. 
Study 
populaƟon 
and 
planned number of subjects 
Nine paƟents with relapsed or refractory IgG4-related disease will 
be recruited. 
Inclusion criteria 
To parƟcipate, subjects must meet all of the following criteria: 
1. 
Aged 18 to 75 years, inclusive, regardless of sex. 
2. 
Meet the 2019 ACR/EULAR classiﬁcaƟon criteria for 
IgG4-related disease. 
3. 
Involvement of two or more systems and/or involvement of 
important organs (including but not limited to the pancreas, 
bile ducts, kidneys and dura mater). 
4. 
Relapsed or refractory IgG4-related disease: remaining in an 
acƟve disease state aŌer at least 3 months of glucocorƟcoid 
plus rituximab therapy or recurrence of disease acƟvity aŌer 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 7 - 
remission; inability to taper glucocorƟcoids or relaƟve 
contraindicaƟons to glucocorƟcoid use (including diabetes, 
hypertension, osteoporosis, etc.). 
5. 
Important organ funcƟon meeƟng the following condiƟons: 
♦ 
Bone marrow: (i) neutrophil count ≥1×10^9/L (excluding 
disease-related neutropenia); (ii) hemoglobin ≥60 g/L. 
♦ 
HepaƟc funcƟon: ALT≤3×ULN (elevaƟon caused by 
disease may be excluded); AST≤3×ULN (elevaƟon caused 
by disease may be excluded); TBIL≤1.5×ULN (elevaƟon 
caused by disease may be excluded). 
♦ 
Renal funcƟon: creaƟnine clearance (CockcroŌ–Gault 
formula) ≥30 ml/min (excluding acute decline due to 
disease). 
♦ 
CoagulaƟon: internaƟonal normalized raƟo (INR) ≤ 
1.5×ULN, prothrombin Ɵme (PT) ≤ 1.5×ULN 
♦ 
Cardiac funcƟon: stable hemodynamics. 
6. 
Women of childbearing potenƟal and male subjects with 
partners of childbearing potenƟal must use medically 
accepted contracepƟon or abstain during study treatment and 
for at least 12 months aŌer the end of treatment. Women of 
childbearing potenƟal must have a negaƟve serum HCG test 
within 7 days before enrollment and must not be 
breasƞeeding. 
7. 
Voluntary parƟcipaƟon in this clinical study with signed 
informed consent and willingness to comply with study 
procedures and follow-up. 
8. 
Patent superﬁcial peripheral veins adequate for intravenous 
infusion. 
Exclusion criteria 
Subjects will be excluded if any of the following criteria are met: 
1. 
History of severe drug allergy or allergic consƟtuƟon. 
2. 
Current or suspected uncontrollable or treatment-requiring 
fungal, bacterial, viral or other infecƟons. 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 8 - 
3. 
Central nervous system disease (excluding disease-related 
epilepsy, psychosis, organic brain syndrome, cerebrovascular 
accident, encephaliƟs or central nervous system vasculiƟs). 
4. 
Cardiac insuﬃciency that precludes parƟcipaƟon. 
5. 
Congenital immunoglobulin deﬁciency. 
6. 
Congenital malformaƟon or nutriƟonal disorder causing 
severe organ impairment. 
7. 
History of malignancy within the past ﬁve years. 
8. 
End-stage renal failure. 
9. 
PosiƟve hepaƟƟs B surface anƟgen and hepaƟƟs B core 
anƟbody with HBV-DNA Ɵters above the assay limit of 
detecƟon; posiƟve hepaƟƟs C anƟbody with HCV-RNA 
posiƟvity; posiƟve human immunodeﬁciency virus anƟbody; 
posiƟve syphilis serology. 
10. Psychiatric disorders or severe cogniƟve impairment. 
11. ParƟcipaƟon in other clinical trials within three months before 
enrollment. 
12. Receipt of any invesƟgaƟonal drug within 12 weeks before 
screening or within ﬁve half-lives of the agent (whichever is 
longer). 
13. Pregnant or intending to become pregnant. 
14. Any other reason deemed by the invesƟgator to preclude 
enrollment. 
InvesƟgaƟonal drug, dose 
and administraƟon 
Three dose cohorts of anƟ-BCMA–CD19 CAR-T cell injecƟon 
(1×10^6, 2×10^6 and 3×10^6 CAR-T cells/kg) will be evaluated 
sequenƟally, with the total number of cells allowed to vary by ± 
20%. The product is administered intravenously. The invesƟgator 
may adjust the dose according to clinical judgment. 
StaƟsƟcal methods 
AŌer compleƟon of the study and locking of the database, data will 
be analyzed by the collaborator or a designated contract research 
organizaƟon. StaƟsƟcal programming and analyses will be 
performed using SAS and/or other validated staƟsƟcal soŌware. 

An Exploratory Study of AnƟ-BCMA-CD19 CAR-T Cell InjecƟon in Relapsed/Refractory IgG4-RD 
Protocol: V1.0 
301_RHUMA 
 
Study ID: 2025-07-15 
- 9 - 
IPD Sharing Plan 
De-idenƟﬁed individual parƟcipant data (IPD) — including baseline 
characterisƟcs, outcome measures, adverse events, and laboratory 
results — will be shared, along with the ﬁnal study protocol, 
informed consent form, and staƟsƟcal analysis plan. Access will be 
granted to qualiﬁed researchers from academic or medical 
insƟtuƟons upon submission of a scienƟﬁcally sound and ethically 
appropriate proposal. Requests will be reviewed by the sponsor and 
principal invesƟgator. Approved researchers must sign a data use 
agreement (DUA). Data will be available aŌer publicaƟon of the 
main results or within 6 months aŌer study compleƟon (whichever 
is earlier), ﬁrst hosted on the principal invesƟgator’s GitHub 
repository and later transferred to a secure insƟtuƟonal plaƞorm.