CD19/BCMA HLA-independent TCR-T Cell Therapy for Refractory/Moderate-to-severe Systemic Lupus Erythematosus

Systemic Lupus Erythematosus Clinical Trial

Official title:

Clinical Study of the Safety and Efficacy of CD19/BCMA HLA-independent TCR-T Cell Therapy for Refractory/Moderate-to-severe Systemic Lupus Erythematosus

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06349343
• Other study ID #: UHCT230949
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: April 2024
• Est. completion date: January 2026

Study information

• Verified date: March 2024
• Source: Wuhan Union Hospital, China
• Contact: Qiubai Li, Professor
• Phone: 85726808
• Email: qiubaili[@]hust.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to explore the safety and efficacy of cluster of differentiation 19 (CD19)/B cell maturation antigen (BCMA) human leukocyte antigen (HLA)-independent T cell receptor (TCR) -T therapy in refractory/moderate-to-severe systemic lupus erythematosus(SLE).

Description:

The prognosis of patients with refractory/moderate-to-severe systemic lupus erythematosus (SLE) remains poor, due to two major therapeutic obstacles: (1) current treatment strategies including glucocorticoids, immunosuppressive agents, biological agents, are still difficult to achieve disease control, making the disease condition of some patients continue to be active or even worse; (2) some patients are unable to wean themselves off glucocorticoid and face the risk of numerous adverse effects caused by long-term glucocorticoid dependence, such as glucocorticoid-related diabetes, femoral head necrosis, hypertension, stress ulcers, and infection, etc. Therefore, there is a strong unmet clinical need for more effective treatment for patients suffering from refractory/moderate-to-severe SLE. Several preclinical and clinical studies have shown the efficacy of chimeric antigen receptor T (CAR-T) cell therapy in SLE. Compared with traditional CAR-T cell therapy, human leukocyte antigen (HLA)-independent T cell receptor (TCR) cell therapy can induce a controllable immune response and maintain a better response durability due to the mechanism of activation and regulation of the natural T cell antigen receptor, while releasing a lower level of cytokines, which can effectively minimizes toxicities. The aim of this study is to investigate the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of cluster of differentiation 19 (CD19)/B cell maturation antigen (BCMA) HLA-independent TCR-T cell therapy in refractory/moderate-to-severe SLE. Patients with refractory/moderate-to-severe SLE will be invited to participate in the study, to receive CD19/BCMA HLA-independent TCR-T cell intravenous infusion and follow-up visits of up to 1 years after enrollment. Given that the pretreatment chemotherapy (fludarabine,cyclophosphamide) of CAR-T therapy in current SLE clinical studies is mostly based on experiences in hematologic malignancies, which may cause severe complications such as infection, there is a lack of evidence-based rationale for patients with SLE to receive pretreatment chemotherapy. This study will explore the feasibility of TCR-T cell therapy without pretreatment chemotherapy in the treatment of refractory/moderate-to-severe systemic lupus erythematosus.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: January 2026
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Participants or their legal guardians understand and voluntarily sign the informed consent form, and be able to complete all the documents, procedures, follow-up examinations and treatments specified in the study protocol, with good compliance;

2. Age range from 18 to 70 years old, regardless of gender;

3. Participants diagnosed with SLE according to the American College of Rheumatology (ACR) 1997 revised criteria for SLE at least 24 weeks prior to screening;

4. Refractory/moderate-to-severe SLE needs to meet the following criteria at screening:

SELENA-SLEDAI score = 6 points; PGA = 1 points; BILAG-2004 organ system scores of at least 1 A or 2 B;Have received at least 12 weeks of standardized treatment for SLE prior to screening but lack efficacy;

5. Participants with fertility agree to take effective contraceptive measures throughout the study and within 3 months after the last follow-up visit.

Exclusion Criteria:

1. Diagnosis of active severe lupus nephritis within 8 weeks prior to screening, requiring medications prohibited by the research protocol for active nephritis, hemodialysis or prednisone = 100 mg/d, or equivalent glucocorticoid therapy for =14 days;

2. Any attempted suicide or suicidal ideation within the past year prior to screening;

3. Presence of SLE or non-SLE related central nervous system diseases or pathological changes within 8 weeks prior to screening;

4. Previous or current diagnosis of non-SLE-related inflammatory arthropathy or skin diseases;

5. History of vital organ transplantation or hematopoietic stem cell/or bone marrow transplantation;

6. History of lymphoproliferative diseases;

7. Subjects with malignancy within 5 years prior to screening;

8. Have received plasma exchange, plasma separation, hemodialysis, or intravenous immunoglobulin (IVIG) within 14 days prior to screening;

9. Other autoimmune diseases requiring systemic therapy;

10. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the lower limit of research institution's test range. Subjects with positive hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV) antibodies, or syphilis;

11. Active or latent tuberculosis at screening;

12. Abnormalities in major organ function at screening;

13. Previous or current diagnosis of acute or chronic illnesses unrelated to SLE with obviously unstable or uncontrollable clinical symptoms;

14. Severe lupus lung damage at screening;

15. Severe lupus cardiac damage at screening;

16. Presence of uncontrollable infections at screening, requiring antibiotic therapy;

17. Have received live/attenuated vaccination within 4 weeks prior to screening or plan to receive live/attenuated vaccination throughout the study;

18. Have received intra-articular, intramuscular or intravenous glucocorticoids within 4 weeks prior to screening;

19. Have received any commercially available Janus kinase (JAK) inhibitor or Bruton tyrosine kinase (BTK) inhibitor within 12 weeks prior to screening;

20. Have received B-cell targeted therapy prior to screening;

21. Have received a biologic agent other than B-cell targeted therapy within 5 half-lives prior to screening;

22. Previously received therapies with CAR-T cells or other genetically modified T cells;

23. Have received therapeutic dose of corticosteroids within 7 days prior to leukapheresis or within 72 hours prior to infusion;

24. Subjects that have donated blood for = 400mL or had a significant blood loss equivalent to at least 400mL within 4 weeks prior to screening, or have received blood transfusion within 8 weeks, or plan to donate blood during the study period;

25. History of =grade 2 bleeding within 4 weeks prior to screening or need for long-term continuous anticoagulant therapy;

26. Subjects that have undergone any major surgeries within 12 weeks prior to screening, or those who are scheduled to undergo major surgery during the study period;

27. History of drug abuse within 12 weeks prior to screening;

28. Female subjects who are pregnant or lactating, or intend to conceive within 2 years after the cell infusion; male patients whose female partners intend to conceive within 2 years after the cell infusion;

29. History of any significant drug allergy or intolerance;

30. Subjects that have participated in other clinical trials within 3 months prior to screening and/or currently participated in other clinical trials (those who do not receive study drugs are excluded);

31. Presence of other circumstances that make the subjects not eligible for participation in the study, in the opinion of the researchers.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

Biological:
• CD19/BCMA Hi-TCR-T cell therapy
CD19/BCMA Hi-TCR-T cell will be infused intravenously at the dose of 1×10^6 cells/kg.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Wuhan Union Hospital, China

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability	Safety and tolerability will be assessed by incidence and severity of adverse events (AEs) and serious AEs (SAEs). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are graded by ASTCT criteria, other AEs are assessed by CTCAE V5.0 criteria	Within 1 years after TCR-T cell infusion
Secondary	Proportion of subjects with SRI-4 response	SRI-4 response is defined as: 1) the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score decrease by no less than 4 points from baseline; 2) the British Isles Lupus Assessment Group (BILAG) score with no new A domain score and no more than 1 new B domain score compared to baseline; 3) the Physician Global Assessment (PGA) score increase less than 0.3 point from baseline.	Within 1 years after TCR-T cell infusion(month 1, month 3, month 6, month 9, month 12)
Secondary	Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline	Range [0, 105],higher score represents worse disease activity	Within 1 years after TCR-T cell infusion(month 1, month 3, month 6, month 9, month 12)
Secondary	Changes in the BILAG-2004 score from baseline	Range [0, 72],higher score represents worse disease activity	Within 1 years after TCR-T cell infusion(month 1, month 3, month 6, month 9, month 12)
Secondary	Changes in the Physician Global Assessment (PGA) score from baseline	Range [0, 3],higher score represents worse disease activity	Within 1 years after TCR-T cell infusion(month 1, month 3, month 6, month 9, month 12)
Secondary	Pharmacokinetics (PK)	Concentration of TCR-T cell in peripheral blood will be evaluated	Within 1 years after TCR-T cell infusion(per 3 days in month 1, per month in month 2 - month 12)
Secondary	Pharmacodynamics (PD)	Pharmacodynamics (PD) will be assessed by levels of cytokines(IL-2?IL-6?IL-10?IFN-?), changes of lymphocyte subsets, immunological indexes(IgG?IgM?IgA?IgE) in peripheral blood	Within 1 years after TCR-T cell infusion(per 3 days in month 1, per month in month 2 - month 12)