cd19/bcma car-t cell therapy for refractory/moderate-to-severe systemic lupus erythematosus

Conditions: Systemic Lupus Erythematosus

Summary: the purpose of the study is to explore the safety and efficacy of cluster of differentiation 19 (cd19)/b cell maturation antigen (bcma) car-t cell therapy in refractory/moderate-to-severe systemic lupus erythematosus(sle).

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. 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) car-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 car-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 car-t cell therapy without pretreatment chemotherapy in the treatment of refractory/moderate-to-severe systemic lupus erythematosus.

Eligibility criteria:
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 2019 european league against rheumatism (eular)/the american college of rheumatology (acr) sle criteria 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.

Keywords: refractory/moderate-to-severe systemic lupus erythematosus car-t cell therapy cd19 bcma