Study of Therapeutic Efficacy of Anti-CD19 CAR-T Cells in Children With Refractory Systemic Lupus Erythematosus

A Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor T Cell Injection Targeting CD19 Gene in the Treatment of Refractory Systemic Lupus Erythematosus in Children

This is an investigator-initiated trial aimed at assessing the safety and efficacy of anti-CD19 CAR-T cells in the treatment of childhood-onset refractory systemic lupus erythematosus.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus; CAR-T Cell Therapy
• Intervention / Treatment: Biological: anti-CD19-CAR-T cells

Detailed Description

Systemic lupus erythematosus (SLE) is a serious autoimmune disease that can lead to extensive damage in multiple organs and systems, ultimately resulting in disability and even death. Children with SLE are particularly at risk of organ damage, especially to the kidneys, and tend to have a more severe and protracted course of the disease compared to adults.

Currently, the primary treatment for SLE relies on glucocorticoids and immunosuppressants to alleviate symptoms. However, due to the absence of a curative treatment, patients often require lifelong medication. In recent years, biological agents such as belimumab and rituximab have been introduced for the treatment of SLE, but these agents cannot completely eliminate autoimmune B cells in the bone marrow, leading to unsatisfactory overall outcomes. Furthermore, stopping the drugs can lead to relapse, and there is still no cure for SLE, leaving patients facing the challenges of lifelong medication and an incurable disease.

Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Clinical studies have demonstrated that targeted CD19 CAR-T cells hold significant therapeutic potential for SLE. These cells effectively slow down the pathological progression of SLE and can also effectively treat severe cases. Furthermore, targeted CD19 CAR-T cells are also expected to restore the immune system in SLE patients, potentially allowing them to discontinue lifelong medication and avoid serious long-term side effects of drugs like hormones and immunosuppressants. The purpose of this study is to assess the safety and efficacy of the anti-CD19 CAR-T cells in the treatment of childhood-onset refractory SLE.

• Study Type: Interventional
• Enrollment (Estimated): 19
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jiahua Mao, MD; Phone Number: 13516819071; Email: maojh88@zju.edu.cn
• Study Contact Backup: Name: Xue He, MD; Phone Number: 15088688407; Email: 6511009@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310052
      • Recruiting
      • Children's Hospital, Zhejiang University School of Medicine
      • Contact: Xue He; Phone Number: 15088688407; Email: 6511009@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age:5-18 years old(including threshold);
2. Diagnosed with SLE according to the 2019 EULAR/ACR SLE classification criteria；Still in moderate to severe disease activity despite ≥3M of high dose glucocorticoids(prednisone≥1mg/kg/d or other equivalent amount of other steriod ), hydroxychloroquine and at least 2 of the following treatments(cyclophosphamide, MMF, azathioprine, methotrexate, cyclosporin, tacrolimus, sirolimus, leflunomide, telitacicept, Beliumab, and rituximab); or Intolerant to standard treatments;
3. SLEDAI 2K score≥8 points;

4. The functions of important organs are basically normal:

   Cardiac function: Left ventricular ejection fraction (LVEF) ≥55% with no obvious abnormality in electrocardiogram; Renal function: eGFR≥30ML/min/1.73m2； Liver function: Asparagus cochinchinensis transase (AST) and Alanine Aminotransferase (ALT)≤3.0 ULN, Total Bilirubin (TBIL) in serum ≤2.0×ULN; Lung function: No serious lung lesions, SpO2≥92%;

5. Met the standards of leukapheresis or intravenous blood collection, No contraindication for cell collection;
6. Negative pregnancy test for female Subjects of childbearing age, agree to take effective contraceptive measures the first year after CAR-T infusion;
7. Participants or their guardians agrees to participate in the clinical trial and sign the informed consent form which indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.

Exclusion Criteria:

1. Received CAR T cell therapy previously;
2. Central nervous system (CNS) disease: CNS neurolupus requires intervention within 60 days);
3. Severe acute nephritis: Patients who have accepted or was undergoing renal replacement therapy within 3 months prior to transfusion; Or in the investgator's opinion, patients who is likely to have significant kidney disease within 3 moths of the study which need high dose glucocorticoid (prednisone dose≥1mg/kg/day or equivalent amount of other steriod), cyclophosphamide, or MMF treatment;
4. Have a history of congenital heart disease or acute myocardial infarction within 6 months prior to screening; Or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); Or combined with moderate to massive pericardial effusion, serious myocarditis, etc; Or patients with unstable vital signs who need hypertensive drugs；
5. Suffer from other diseases that require long-term use of glucocorticoid or high-dose of immunosuppressive agents;
6. Uncontrollable infection, or active infection that requires systemic treatment within 1 week prior to screening；
7. History of organ transplantation or hematopoietic stem cell transplantation, or ≥Grade 2 GVHD within 2 weeks prior to screening；
8. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal reference value range; Or hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal reference value range; Or positive for human immunodeficiency virus (HIV) antibodies; Or syphilis test positive; Or cytomegalovirus (CMV) DNA test positive;
9. Received live vaccine within 4 weeks before screening;
10. Tested positive in Blood pregnancy test；
11. Previous or concurrent malignancy；
12. Patients who participated in other clinical study within 3 months prior to enrollment;
13. Any other conditions that the investigators deem it unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CAR-T treatment group; The trial consists of two phases, Dose Exploration (Part A) and Dose Expansion (Part B). In Part A, three dose groups (1×105/kg, 3×105/kg, 5×105/kg) are set up, starting from the low dose group to explore the safe and effective dose. If the optimal effective dose is still not explored in the highest dose group, the dose can be increased according to the situation, and the highest dose is no more than 10×105/kg. Upon the completion of Part A, 1~2 optimal doses are selected by the comprehensive judgment of the investigator and the technical partner to enter into the Part B stage. Each dose group will then be enrolled in 3~6 cases to continue to validate the safety and efficacy. A total enrollment of 10-19 patients is expected in the whole process of the trial.

Biological: anti-CD19-CAR-T cells; Three dose groups (1×105/kg, 3×105/kg, 5×105/kg) were set up, starting from the low dose group climbing to explore the safe and effective dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety of CAR-T cell in refractory childhood-onset Systemic Lupus Erythematosus	Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs as assessed by CTCAE v5.0.	3 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The efficiency of CAR-T cell in refractory childhood-onset Systemic lupus Erythematosus.	Number of patients with SRI-4 response: including SLEDAI-2K ≥ 4-Point improvement, PGA with no worsening (<0.3-point increase), BILAG 2004 with no new A domain score and no more than 1 new B domain scores.	3 Months
Cellular kinetics	CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood.	6 Months
Autoantibody detection	Autoantibody detection up after CD19 CAR-T cells infusion.	24 Months
Duration of disease response (DOR)	The time between the first investigator assessment of remission and the first investigator assessment of progression or death from any cause.	24 Months

Collaborators and Investigators

• Sponsor: The Children's Hospital of Zhejiang University School of Medicine
• Collaborators: Chongqing Precision Biotech Co., Ltd
• Investigators: Principal Investigator: Jianhua Mao, MD, Children's Hospital, Zhejiang University School of Medicine

Publications and helpful links

General Publications

• Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M, Volkl S, Simon D, Kleyer A, Munoz L, Kretschmann S, Kharboutli S, Gary R, Reimann H, Rosler W, Uderhardt S, Bang H, Herrmann M, Ekici AB, Buettner C, Habenicht KM, Winkler TH, Kronke G, Schett G. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132. doi: 10.1038/s41591-022-02017-5. Epub 2022 Sep 15. Erratum In: Nat Med. 2022 Nov 3;:
• Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nat Rev Dis Primers. 2020 Jan 23;6(1):7. doi: 10.1038/s41572-019-0141-9.
• Kansal R, Richardson N, Neeli I, Khawaja S, Chamberlain D, Ghani M, Ghani QU, Balazs L, Beranova-Giorgianni S, Giorgianni F, Kochenderfer JN, Marion T, Albritton LM, Radic M. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med. 2019 Mar 6;11(482):eaav1648. doi: 10.1126/scitranslmed.aav1648.
• Jin X, Xu Q, Pu C, Zhu K, Lu C, Jiang Y, Xiao L, Han Y, Lu L. Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. Cell Mol Immunol. 2021 Aug;18(8):1896-1903. doi: 10.1038/s41423-020-0472-1. Epub 2020 May 29.
• Mougiakakos D, Kronke G, Volkl S, Kretschmann S, Aigner M, Kharboutli S, Boltz S, Manger B, Mackensen A, Schett G. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2021 Aug 5;385(6):567-569. doi: 10.1056/NEJMc2107725. No abstract available.
• Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25.
• Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62. doi: 10.1038/nrclinonc.2017.148. Epub 2017 Sep 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: January 4, 2024
• First Submitted That Met QC Criteria: January 15, 2024
• First Posted (Estimated): January 25, 2024

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Children; CAR-T; Systemic Lupus Erythematosus
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic
• Other Study ID Numbers: STEAM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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