POS0046 PRELIMINARY RESULTS OF AN OPEN-LABEL, MULTICENTRE, PHASE 1/2 STUDY TO ASSESS SAFETY, EFFICACY AND CELLULAR KINETICS OF YTB323 (RAPCABTAGENE AUTOLEUCEL), A RAPIDLY MANUFACTURED CAR T-CELL THERAPY TARGETING CD19 ON B CELLS, FOR SEVERE REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS

Background:

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against multiple self-antigens by autoreactive B cells. Patients with severe refractory SLE (srSLE) exhibit failure to respond to treatments, progressive organ damage, and high mortality. Recent case reports indicated that traditionally manufactured CD19-directed chimeric antigen receptor T-cell (CAR T-cell) therapies may result in full clinical remission in srSLE.[1,2] YTB323 (rapcabtagene autoleucel) is a novel, rapidly manufactured, autologous CD19-directed CAR T-cell therapy, that demonstrated improved safety and efficacy in haematological malignancies in comparison to traditionally manufactured CAR T-cell therapies.[3]

Objectives:

To determine the safety, efficacy and cellular kinetics of YTB323, a CD19-directed CAR T-cell therapy, in patients with srSLE in a clinical trial setting.

Methods:

An open-label, single-arm, multicentre phase 1/2 study (NCT05798117) to assess the safety, efficacy and cellular kinetics of YTB323 in participants with srSLE is currently ongoing. YTB323 treatment is a single administered dose of 12.5×10⁶ CAR-positive viable T cells following lymphodepletion with cyclophosphamide/fludarabine. Collected safety data include adverse events, severe adverse events and deaths, vital signs, electrocardiogram and laboratory assessments. Cellular kinetics data are monitored by quantitative polymerase chain reaction and flow cytometry, and pharmacodynamics assessments include levels of B cells, T cells, immunoglobulin (Ig)G, IgA, IgM, complement C3, complement C4 and autoantibodies. Preliminary efficacy is assessed using disease activity scores, Physician's Global Assessment (PhGA) and renal outcome measures.

Results:

Between April and December 2023, six patients with srSLE received YTB323 treatment. Safety, pharmacokinetics/pharmacodynamics (PK/PD) and preliminary efficacy data for the first three patients who received treatment (data cutoff: August 2023), and acute safety data for all six patients who received treatment (data cutoff: December 2023) are presently available. Transient lymphodepletion-related cytopenia (grade 3 or 4) was observed in all six patients as expected, including anaemia in three patients and neutropenia in five patients. Hypogammaglobulinaemia, which did not require intravenous immunoglobulin treatment, was a common adverse event. Cytokine release syndrome (CRS) was observed in four of six patients. All CRS events were grade 1 or 2 and resolved following treatment with tocilizumab. No events of immune cell-associated neurotoxicity syndrome were reported. Infectious complications included pneumonia in one patient (grade 2). For the first three patients (data cutoff: August 2023), PK/PD studies revealed peak expansion of CAR T cells approximately 13–21 days post-infusion and deep B-cell depletion, with subsequent B-cell recovery. Preliminary efficacy data for the first three patients indicated considerable reductions in SLE Disease Activity Index (SLEDAI) (Figure 1a) and PhGA (Figure 1b) accompanied by improvements in relevant disease biomarkers such as autoantibodies (Figure 1c), complement levels (Figure 2a and b), and proteinuria. Additional data from extended follow-up of all enrolled patients will be available at the next data cutoff (April 2024).

Conclusion:

Preliminary data from this clinical trial suggest favourable safety, CAR T-cell expansion, B-cell depletion and initial efficacy of YTB323 in srSLE, supporting its continued evaluation. Data from additional enrolled patients and continued follow-up are being generated as the study progresses.

REFERENCES:

[1] Mackensen A, et al. Nat Med. 2022;28:2124–32. [2] Taubmann J, et al. The EULAR Journal. 2023;93. [3] Dickinson MJ, et al. Cancer Discov. 2023;13:1982–97.

Acknowledgements:

The authors thank Rangariroyashe Chipika (Novartis Ireland Limited, Dublin, Ireland) and Nicola Harris (Novartis Pharmaceuticals UK Ltd, London, UK) for editorial and medical writing support, which was funded by Novartis Pharma AG, Basel, Switzerland in accordance with the Good Publication Practice (GPP 2022) guidelines (http://www.ismpp.org/gpp-2022). This study was sponsored by Novartis Pharma AG, Basel, Switzerland.

Disclosure of Interests:

Josefina Cortés-Hernández GSK, Astrazeneca, Otsuka, Pere Barba Jazz Pharmaceuticals, Miltenyi Biomed, Nektar, Novartis, Pierre Fabre, Allogene, Amgen, Incyte, Kite/Gilead, BMS/Celgene, Jose-Maria Alvaro-Gracia Abbvie, GSK, BMS, Novartis, Astra-Zeneca, Pfizer, UCB and Galapagos, Abbvie, GSK, BMS, Novartis, Astra-Zeneca, Pfizer, UCB and Galapagos, Mi Kwon Pfizer, Jazz, Gilead, Incyte, Julia Weinmann-Menke Astra Zeneca, Novartis, Chiesi, GSK, Boehringer-Ingelheim, Miltenyi, Vifor, Bayer, Otsuka, Takeda, Esanum, Bayer, Novartis, Boerhinger-Ingelheim, Chiesi, Astra Zeneca, Otsuka und GSK, GSK, Toray, Miltenyi, Diamed, Eva Wagner-Drouet Kite Gilead, Kite Gilead, Novartis, Takeda, MSD, Celgene, Janssen, Ozana Fischer Novartis, Novartis, Beata Kovacs Novartis, Frédérique Chaperon Novartis, David Pearson Novartis, Roche, Novartis, Tiina Kirsilä Novartis, Novartis, Novartis, Chih-Yung Sean Lee Novartis, Novartis, Clive Drakeford Novartis, Novartis, Peter Gergely Novartis, Novartis, Giulio Cavalli Novartis, SOBI, Pfizer, Novartis, Novartis, Novartis, SOBI, Pfizer, Tamas Shisha Novartis, Novartis.