A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis

Study Overview
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Brief Summary
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A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Subjects With Refractory Lupus Nephritis

Detailed Description
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide spectrum of organ involvement and disease severity. Renal involvement (categorized as lupus nephritis [LN]) may occur in approximately 50% of SLE patients and is marked by proteinuria, microscopic hematuria, and varying degrees of renal insufficiency. B cells play a central role in the pathogenesis of SLE and LN, with autoantibodies developing as an early finding, and local, tissue resident B cells producing pathogenic autoantibodies and driving inflammation and tissue damage over time. CD19-targeted chimeric antigen receptor (CAR) T cells harness the ability of cytotoxic T cells to directly and specifically lyse target cells to effectively deplete B cells in the circulation and in lymphoid and potentially non-lymphoid tissues. KYV-101, a fully human anti-CD19 CAR T-cell therapy, will be investigated in adult subjects with refractory lupus nephritis.

Official Title
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A Phase 1, Open-Label, Multicenter Study of KYV-101, an Autologous Fully-Human Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis

Conditions
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Lupus Nephritis, Lupus Nephritis - World Health Organization (WHO) Class III, Lupus Nephritis - WHO Class IV

Intervention / Treatment
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* Biological: KYV-101 anti-CD19 CAR-T cell therapy
* Drug: Standard lymphodepletion regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Clinical diagnosis of SLE according to 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria Biopsy-proven proliferative LN Class III or IV according to 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria Positive anti-nuclear antibody (ANA) (titer ≥1:80 ), anti-dsDNA (≥30 IU/mL on enzyme-linked immunosorbent assay [ELISA]), or anti-Smith at screening or by documented medical history Up to date on recommended vaccinations, including against coronavirus disease 2019/ severe acute respiratory syndrome coronavirus 2 (Covid-19/SARS-Cov-2), per Centers for Disease Control and Prevention (CDC) or institutional guidelines for immune compromised individuals Exclusion Criteria: Rapidly progressive glomerulonephritis; history of or currently active severe central nervous system (CNS) lupus, including cerebritis, cerebrovascular accident, and seizures Prior treatment with cellular therapy (CAR-T) or gene therapy product directed at any target History of allogeneic or autologous stem cell transplant Evidence of active hepatitis B or hepatitis C infection Positive serology for HIV Primary immunodeficiency History of splenectomy History of stroke, seizure, dementia, Parkinson's disease, coordination movement disorder, cerebellar diseases, psychosis, paresis, aphasia, and any other neurologic disorder investigator considers would increase the risk for the subject Impaired cardiac function or clinically significant cardiac disease Previous or concurrent malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to screening) In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to screening A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 5 years prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KYV-101 CAR-T cells with lymphodepletion conditioning<br>Dosing with KYV-101 CAR T cells | Biological: KYV-101 anti-CD19 CAR-T cell therapy<br>* KYV-101 anti-CD19 CAR-T cell therapy<br>Drug: Standard lymphodepletion regimen<br>* Standard lymphodepletion regimen<br>* Other names: Fludarabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence adverse events (AEs) and laboratory abnormalities |  | Up to 24 months | 
| Frequency of dose limiting toxicities at each dose level |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetics (PK) | Levels of KYV-101 CAR-positive T cells in the blood | Up to 2 years | 
| To characterize the pharmacodynamics (PD) | Levels of B cells in the blood | Up to 2 years | 
| To characterize the pharmacodynamics (PD) | Levels of cytokines in serum | Up to 2 months | 
| To evaluate disease related biomarkers | Levels of anti-double stranded DNA (anti-dsDNA) in serum | Up to 2 years | 
| To evaluate disease related biomarkers | Levels of complement C3, C4 in serum | Up to 2 years | 
| To evaluate efficacy | Complete renal response rates (CRR) | 12, 24, and 52 weeks | 
| To evaluate efficacy | Time to CRR | Up to 2 years | 
| To evaluate efficacy | Time from first achieved CRR to disease worsening or end of study | Up to 2 years | 
| To evaluate the immunogenicity (humoral response) of KYV-101 | Percentage of participants who develop anti-KYV-101 antibodies by immunoassays | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KYV-101, glomerulonephritis, autoimmune disease, anti-CD19 CAR-T therapy, cellular therapy