Background: Autologous and allogeneic chimeric antigen receptor (CAR) T and NK cell therapies have shown promise for the treatment of a suite of autoimmune disorders. To date, cellular CAR therapies are reliant on pretreatment with conditioning chemotherapies (CCT) to support product activity. CCT supports CAR T and NK cell persistence through multiple mechanisms, including access to essential homeostatic cytokines and depletion of key immune populations that can attack and potentially eliminate CAR T-cell products, thereby limiting product persistence and activity. However, because CCTs are harsh treatments with extreme side-effects, and potential long-term consequences to reproductive health, therapies with a requirement for CCT, may not be ideal for all patients with autoimmune disorders. FT522 is an induced pluripotent stem cell (iPSC)-derived off-the-shelf, natural killer (NK) cell therapy designed to function without the need for CCT. FT522 incorporates a CD19-targeted CAR; CD38 knockout to enhance metabolic fitness; an alloimmune defense receptor (ADR) targeting 4-1BB to prevent immune rejection; a high-affinity non-cleavable CD16 (hnCD16) Fc receptor to maximize antibody-dependent cellular cytotoxicity (ADCC) when cotreating with therapeutic antibodies; and an IL-15/IL-15 receptor fusion protein (IL15RF) to offer cell-intrinsic cytokine support and function.

Objectives: To determine whether FT522, in the absence of CCT, can function, persist, and deplete B cells for the effective treatment of autoimmune diseases.

Methods: Preclinical in vitro studies of FT522 were carried out using unmatched systemic lupus erythematosus (SLE) donor peripheral blood mononuclear cells (PBMC) to investigate the capacity of FT522 to eliminate SLE donor B cells. A clinical study of FT522 is being investigated in a multicenter Phase I clinical trial in patients with relapsed/refractory (R/R) B-cell lymphomas (BCL) (NCT05950334). FT522 is administered in three doses (Days 1, 4, and 8) either with CCT (fludarabine 30 mg/m ² and cyclophosphamide 500 mg/m ² , Days -5 to -3) or without CCT. Both regimens include rituximab(R) 375 mg/m ² (Day -4). Whole blood samples are collected at protocol defined timepoints to allow for comparison of product function and persistence with and without CCT.

Results: Preclinical data demonstrate that FT522 is capable of rapid and potent depletion of SLE donor CD19+ B cells in vitro. Additionally, in a mixed lymphocyte reaction, FT522 was more effective in eliminating B cells as compared to a primary CAR T cell control without ADR. Interim Phase1 data in R/R BCL (NCT05950334) demonstrated that in the absence of CCT (n=5), FT522 is capable of persisting with peak detection of viable cells between Days 4-11 and persistence during the first two weeks of the treatment cycle. The PK trend is comparable to most CAR containing products, including that of FT522, administered with CCT. Notably, when considering equivalent conditions, FT522 persistence is superior to the prior generation of CAR NK, including in direct comparison at significantly lower doses, i.e. 6x fewer cells introduced still resulted in higher persistence. Notably, each dose of FT522, administered without CCT on Days 1, 4, and 8, maintained the capacity to deplete CD19+ B cells, and did not aberrantly impact other components of the patients’ immune systems. No evidence of cellular or humoral anti-drug responses against FT522 was detected in treated patients. Aligned with anti-B cell activity, clinical benefit was observed following FT522 without CCT administration in a Waldenstrom Macroglobulinemia (WM) patient, including a significant reduction in immunoglobulin M (IgM). Based on clinical proof-of-concept in R/R BCL, a Phase 1 clinical trial across a basket of B cell-mediated autoimmune diseases has been allowed by the FDA, and study launch preparation is ongoing. The study is designed to assess FT522, without administration of CCT to patients, as an add-on to rituximab induction (Regimen A) and in combination with rituximab as an add-on to maintenance therapy (Regimen B). Study status and treatment of subjects will be shared at the time of presentation.

Conclusion: Collectively, our preclinical and early-stage oncology clinical data in R/R BCL demonstrate that FT522 can persist, function, and function, and confer clinical benefit without the need for CCT. Furthermore, the clinical data discussed here supports the application of FT522, without CCT, for B-cell mediated autoimmune diseases.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© 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.