KYSA-1: A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis

Phase 1

Recruiting

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

Interventions: Biological: KYV-101 anti-CD19 CAR-T cell therapy
Drug: Standard lymphodepletion regimen

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

Detailed Description: 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.

Recruitment & Eligibility

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 (COVID-19)/ severe acute respiratory syndrome coronavirus 2 (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 immunotherapy (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:
1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to screening)
2. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to screening
3. A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 5 years prior to screening

Arm && Interventions

Group	Intervention	Description
KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 1)	Standard lymphodepletion regimen	Dosing with KYV-101 CAR T cells
KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 2)	KYV-101 anti-CD19 CAR-T cell therapy	Recommended Phase 2 Dose
KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 1)	KYV-101 anti-CD19 CAR-T cell therapy	Dosing with KYV-101 CAR T cells
KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 2)	Standard lymphodepletion regimen	Recommended Phase 2 Dose

Primary Outcome Measures

Name	Time	Method
Incidence adverse events (AEs) and laboratory abnormalities (Phase 1 and Phase 2)	Up to 2 years
Frequency of dose limiting toxicities at each dose level (Phase 1)	Up to 2 years
To Evaluate efficacy (Phase 2)	Up to 52 Weeks	Complete renal response rates (CRR)

Secondary Outcome Measures

Name	Time	Method
To characterize the pharmacokinetics (PK) (Phase 1 and Phase 2)	Up to 2 years	Levels of KYV-101 CAR-positive T cells in the blood
To evaluate disease related biomarkers (Phase 1 and Phase 2)	Up to 2 years	Levels of complement C3, C4 in serum
To characterize the pharmacodynamics (PD) (Phase 1 and Phase 2)	Up to 2 months	Levels of cytokines in serum
To evaluate efficacy (Phase 1 and Phase 2)	Up to 2 years	Time from first achieved CRR to disease worsening or end of study
To evaluate efficacy (Phase 2)	Up to 52 weeks	Duration of CRR to Week 52 but no less than 12 weeks (duration of remission)
To evaluate the immunogenicity (humoral response) of KYV-101 (Phase 1 and Phase 2)	Up to 2 years	Percentage of participants who develop anti-KYV-101 antibodies by immunoassays
To assess PRO after infusion of KYV-101 (Phase 1 and Phase 2)	Up to 2 years	Change from Baseline in WPAI
To define the Recommended Phase 2 Dose (RP2D) (Phase 1)	Up to 2 years

Locations (6): University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Ohio State University Wexner Medical Center
🇺🇸
Columbus, Ohio, United States
University of Colorado
🇺🇸
Denver, Colorado, United States
Northwell Health
🇺🇸
Great Neck, New York, United States
University of Massachusetts Worcester
🇺🇸
Worcester, Massachusetts, United States
Stanford University Medical Center
🇺🇸
Palo Alto, California, United States