Cortés Hernández, Josefina, Barba, Pere, Linares Alberich, Monica, Fischer, Ozana, Kovacs, Beata, Calzascia, Thomas, Pearson, David, Jordan Garrotte, Ana-Laura, Kirsilae, Tiina, Siegel, Richard, Shisha, Tamas, Cavalli, Giulio and Gergely, Peter (2023) An Open-label, Multi-center, Phase 1/2 Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323, a Rapid Manufacturing CAR-T Cell Therapy Targeting CD19 on B Cells, for Severe Refractory Systemic Lupus Erythematosus: Preliminary Results. An Open-label, Multi-center, Phase 1/2 Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323, a Rapid Manufacturing CAR-T Cell Therapy Targeting CD19 on B Cells, for Severe Refractory Systemic Lupus Erythematosus: Preliminary Results.

Abstract

Background/Purpose
Systemic lupus erythematosus (SLE) is characterized by pathogenic autoreactive B cells producing autoantibodies against multiple self-antigens. Recently, a series of clinical cases suggest that traditionally manufactured anti-CD19 chimeric antigen receptor T cell (CAR-T cell) therapies show potential to promote full clinical remission in severe refractory SLE (srSLE).1,2 This is the first clinical trial to evaluate the preliminary safety and efficacy of anti-CD19 CAR-T cell therapy in patients with srSLE. YTB323 is a novel, rapidly manufactured autologous CAR-T therapy that has shown preserved T cell stemness and enhanced CAR-T cell efficacy in hematological malignancies.3
Methods
An open-label, single-arm, multi-center phase I/II study, CYTB323G12101 (NCT05798117), to assess the safety, efficacy, and cellular kinetics of YTB323 in participants with srSLE is currently ongoing. A sentinel cohort of patients with srSLE (n=3), dosed with 12.5x106 cells at least 28 days apart, were enrolled. The primary endpoint is safety as measured by vital signs, adverse events, laboratory parameters and ECG evaluation. CAR-T cell kinetics were monitored by quantitative PCR and flow cytometry. Further relevant endpoints include changes from baseline levels in circulating B and T cells, autoantibody and complement levels, disease activity scores and renal outcome measures.
Results
Baseline characteristics of patients are summarized in Table 1. Adverse events are shown in Figure 1. No serious adverse events or deaths were reported. Disease worsening requiring treatment occurred in the first patient between apheresis and prior to lymphodepletion. No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. A grade 1 cytomegalovirus reactivation occurred in one patient, which was subsequently resolved. Two patients had cytokine release syndrome (grade 1 or 2); both responded well to tocilizumab treatment and fully recovered. As expected, grade 3 and 4 transient lymphodepletion-related cytopenias were observed in all patients. Grade 2 or 3 hypogammaglobulinemia was observed in two patients; neither event required intravenous immunoglobulin treatment. Cellular kinetics studies showed peak expansion (Tmax) at 13 and 18 days post-infusion for the two patients with data characterizing the expansion phase. Transient T cell and sustained B cell depletion was observed in all patients. Preliminary efficacy data (Figure 2) suggest substantial decreases in SLE Disease Activity Index (SLEDAI) (Figure 2a) and in Physician’s Global Assessment (PhGA) (Figure 2b) in line with improvements in relevant disease biomarkers, such as dsDNA (Figure 2c), complement levels and proteinuria.
Conclusion
Preliminary data from this clinical trial including the first three sentinel patients suggest favorable safety, CAR-T cell expansion, B cell depletion and initial efficacy supporting continuation of the study to evaluate YTB323 in srSLE.

Item Type:	Article
Keywords:	clinical trial, Late-Breaking 2023, Systemic lupus erythematosus (SLE)
Date Deposited:	29 Nov 2023 00:45
Last Modified:	29 Nov 2023 00:46
URI:	https://oak.novartis.com/id/eprint/52002