Background/Purpose: The treatment goals for systemic sclerosis (SSc) are to control disease activity, limit progression of organ damage and decrease long-term morbidity and mortality. Therapies providing durable clinical responses without requiring chronic administration are lacking. Rese-cel (formerly CABA-201) is a fully human, autologous 4-1BB CD19-CAR T cell therapy designed to deeply and transiently deplete CD19 positive cells following a weight-based, single infusion to enable an “immune system reset” with the potential for durable response without chronic immunomodulatory (IM) therapy. RESET-SScTM (NCT06328777) is an ongoing Phase 1/2 trial evaluating rese-cel in 2 independent cohorts of adults with SSc and either severe skin or organ involvement.

Methods: Eligible patients were 18 to 75 years with SSc. A weight-based infusion of 1×106 CAR T cells/kg was administered following preconditioning with fludarabine and cyclophosphamide. All non-glucocorticoid (GC) IM agents were stopped by Day -5. Adverse events, modified Rodnan skin score (mRSS), pulmonary function test (PFTs), nailfold capillaroscopy (NFC) and use of IM medications were evaluated. CAR T cells and B cells were profiled in peripheral blood pre- and post-infusion by digital PCR and flow cytometry, respectively. Serum cytokines were measured using the mesoscale discovery platform. Inguinal lymph node biopsies were taken from SSc-Skin-1 before and 21-days after rese-cel under a biorepository at University of Michigan; tissue was labeled for B cells (CD19, CD20, and PAX5, not shown) and T cells (CD3).

Results: As of 31 March 2025, 2 patients were infused with rese-cel (Table 1); SSc-Skin-2 did not have sufficient follow-up for efficacy or translational assessments. A third patient was recently infused.SSc-Skin-1 had grade 2 cytokine release syndrome (CRS) but no dose-limiting toxicity (DLT) or immune effector cell-associated neurotoxicity syndrome (ICANS). SSc-Skin-2 experienced grade 3 ICANS based on a transient period of isolated confusion without seizures, motor findings, or signs of cerebral edema, which resolved in < 2 days with GC alone.SSc-Skin-1 showed improvement on mRSS, PFT and NFC at 6 months off all IM therapy. MRSS gradually improved from 42 to 34. NFC showed preliminary evidence of improvement of capillary density and size.SSc-Skin-1 exhibited robust expansion of rese-cel that peaked at Day 15 post-infusion and was undetectable by Day 29. Serum IFNγ levels increased post-infusion and peaked prior to rese-cel peak expansion. Peripheral B cells were rapidly reduced in circulation by Day 15 and in lymphoid tissue (Figure 1) at Day 21. B cells reconstituted by 8 weeks post-infusion with a transitional naïve phenotype (CD19+CD20+CD38++CD24++) and switched to predominantly mature naïve by 6 months.

Conclusion: Data from the first SSc patient infused with rese-cel shows early IM-free clinical response and acceptable safety profile in the setting of CAR T cell expansion and complete peripheral and lymph node B cell depletion. These initial data suggest the potential for rese-cel to reset the immune system in SSc, allowing patients to achieve meaningful clinical responses off all IM therapies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reset-ssc-clinical-trial-evaluating-rese-cel-resecabtagene-autoleucel-a-fully-human-autologous-4-1bb-cd19-car-t-cell-therapy-in-systemic-sclerosis/