Background: Achieving sustained drug-free remission in B cell-driven autoimmune diseases remains a substantial unmet medical need. CD19-targeted autologous CAR-T cell therapy, currently indicated for hematological malignancies, has recently demonstrated promising therapeutic efficacy and tolerability in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc) [1, 2]. This new treatment modality provides a potentially transformative therapy for autoimmune diseases. However, the need for apheresis and custom product manufacturing can result in variable product quality and delay in treatment. CNTY-101 is a CD19-targeting, off-the-shelf, clonally derived, and fully characterized induced pluripotent stem cell (iPSC)-derived NK cell therapy product that presents a unique opportunity to overcome some of the challenges of autologous CAR T cell therapy products. CNTY-101 is designed with six (6) precision gene edits which include a CD19-targeting CAR, secreted interleukin-15 (sIL-15) for enhanced persistence, and a set of edits designed to evade allogeneic rejection (Allo-Evasion™ technology). The Allo-Evasion™ edits comprise genetic ablation of beta 2 microglobulin and CIITA to disrupt functional expression of HLA class I and II, and the expression of HLA-E, which can prevent NK cell-mediated rejection [3]. CNTY-101 safety and efficacy are currently being evaluated in two clinical trials: ELiPSE-1, a Phase 1 trial in relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (NCT05336409) [4] and CALiPSO-1, a Phase 1 basket trial in SLE, LN, SSc and IIM (NCT06255028). Here, we present translational evidence for CNTY-101 treatment-induced B cell depletion, lymph node CAR-NK trafficking, as well as initial clinical validation of the Allo-Evasion™ platform that makes CNTY-101 uniquely suited for the treatment of autoimmune diseases.

Objectives: We sought to: 1) Understand the ability of CNTY-101 to kill autoimmune disease-associated B cells ex vivo. 2) Evaluate the ability of CNTY-101 to traffic to lymph nodes and eliminate B cells in patients. 3) Assess whether Allo-evasion ^TM edits confer protection to CNTY-101 in the presence of an intact immune system.

Methods: An in vitro cytotoxicity assay was established using coculture of B cells isolated from healthy donors or donors diagnosed with SLE and SSc, along with CNTY-101 cells or healthy donor-derived CD19 CAR T cells. CNTY-101 or CAR T-specific cytotoxicity against donor B cells was determined by quantitating B cell death by flow cytometry at 24 hours post-coculture. To evaluate CNTY-101 functionality and ability to evade host immunity, samples from patients treated in the dose level 3B cohort (≥1 cycle of three weekly doses of 1 billion cells administered following cyclophosphamide and fludarabine pre-conditioning regimen) of the ELiPSE-1 study were evaluated. To assess CNTY-101 trafficking, lymph node tumor biopsies were interrogated by RNA-ISH with probes specific to the CAR, IFN-γ and TNF-α. B cell, T cell and NK cell absolute counts were determined by flow cytometry on fresh stabilized blood. B cell phenotyping was performed on cryopreserved samples from timepoints where circulating B cells were detected. Persistence of CNTY-101 was determined by longitudinal ddPCR-based detection of transgene promoter sequences in patient plasma-derived cell-free DNA. Serum absolute IL-15 levels were measured using MSD technology.

Results: In vitro, CNTY-101 exhibited robust killing of B cells isolated from healthy donors and donors with SLE and SSc with greater potency compared to primary CAR T cells. In patients from the ELiPSE-1 study, CNTY-101 treatment demonstrated rapid and deep depletion of circulating B cells. In a subset of patients where subsequent B cell reconstitution occurred, the emerging B cells presented a naïve, non-class switched phenotype. Tumor biopsy analyses demonstrated that CNTY-101 cells were capable of trafficking to lymph nodes and expressing cytokines characteristic of immune activation such as IFN-γ and TNF-α. While lymphodepletion resulted in a significant decrease in T and NK cell counts, along with a transient spike in serum IL-15 levels within the 1 ^st week post-infusion, lymphocyte counts and IL-15 levels returned to baseline levels within 8 days post-infusion. Despite the return of immune cells and waning of IL-15 levels, each of the three CNTY-101 infusions (given on Day 1, Day 8, and Day 15) showed comparable persistence and exposure. This data suggests that CNTY-101 can persist independent of endogenous IL-15. Additionally, the initial data is supportive of the Allo-Evasion™ edits preventing CNTY-101 rejection by the host immune system.

Conclusion: Our results provide evidence that CNTY-101, an allogenic cell therapy, both evades host rejection and depletes B cells effectively. Century’s proprietary Allo-Evasion™ technology enables a multi-dose regimen in the presence of restored endogenous NK and T cells which can confer prolonged pharmacological pressure on pathogenic B cells. Collectively, these findings support the clinical development of CNTY-101 in autoimmune diseases in the CALiPSO-1 study.

REFERENCES: [1] Mackensen A, et al. Nat Med. 2022;28:2124-2132.

[2] Muller F, et al. NEJM 2024;390:687-700.

[3] Mendonca M, et al. 2024 ASGCT Abstract #1815.

[4] Patel K, et al. 2024 ASCO Abstract #7023.

Acknowledgements: Sam Kelly and Gloria Jih contributed equally to this work.

Disclosure of Interests: Sam Kelly Century Therapeutics, Gloria Jih Century Therapeutics, Kile McFadden Century Therapeutics, Thomas Brigman Century Therapeutics, Stephanie Yee Century Therapeutics, Mark Mendonca Century Therapeutics, Kaitlin Idank Century Therapeutics, Liam Campion Century Therapeutics, Kevin Bullaughey Century Therapeutics, Dustin Whitney Century Therapeutics, Nikolaus Trede Century Therapeutics, Sarah Rothman BMS, Century Therapeutics, Elizabeth Devlin Celgene/BMS, Celgene/BMS, Century Therapeutics, Anne Stevens Amgen, Johnson & Johnson, Acelyrin, Johnson & Johnson, Acelyrin, Century Therapeutics, Seagen, Amgen, Kineta, Inc., Adrienne Farid Century Therapeutics, Celgene Corporation, Roche Pharmaceuticals, GSK, Hongxia Zhang GSK, Century Therapeutics, Indu Ramachandran Century Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.