Background: 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 immunosuppressive (IS) drugs are lacking. CD19-targeting chimeric antigen receptor (CAR) T cells have achieved durable drug-free responses in SSc patients in an academic program. Rese-cel (formerly referred to as CABA-201) is a fully human, autologous 4-1BB anti-CD19-CAR T cell therapy, designed to deeply and transiently deplete CD19 positive cells following a weight-based, one-time infusion. This approach may enable an “immune system reset” with the potential for durable response without chronic immunosuppression. RESET-SSc TM (NCT06328777) is an ongoing Phase 1/2 trial evaluating rese-cel in 2 independent cohorts of adults diagnosed with SSc with either severe skin or organ involvement.
Objectives: The primary objective is safety and tolerability within 28 days of infusion. Secondary objectives include clinical outcomes (ie., modified Rodnan skin score (mRSS), pulmonary function tests and use of IS agents) and translational assessments (ie., CAR T cell pharmacokinetics and impact on peripheral B-cell populations).
Methods: Eligible patients are ≥18 to ≤75 years with SSc, disease duration of ≤7 years from first non-Raynaud’s phenomenon symptoms, with either severe skin or organ (lung, heart or kidney) involvement. A single weight-based infusion of 1x10 6 CAR T cells/kg is administered following a preconditioning regimen (fludarabine 25 mg/m 2 /d on Days -5, -4 and -3, and cyclophosphamide 1,000 mg/m 2 on Day -3). All non-glucocorticoid IS agents are stopped by Day -5. Patients at the University of Michigan may also participate in a separate biorepository study in which patient samples, including lymph node biopsies, are collected for exploratory analyses.
Results: A total of 3 patients have been enrolled. 1 patient has been treated with rese-cel and has completed 3 months of follow-up in the RESET-SSc TM trial in the severe skin cohort (Table 1). Two patients have undergone leukapheresis and are expected to receive rese-cel in early 2025.
Table 1.
The first patient tolerated rese-cel with no dose-limiting toxicity or immune effector cell-associated neurotoxicity syndrome (ICANS). The patient experienced grade 2 cytokine release syndrome (CRS), manifesting as fever and hypotension which resolved following intravenous fluids without requiring tocilizumab. The patient has maintained a drug-free response through 3 months of follow-up. Skin thickness on mRSS has gradually improved from 42 at baseline to 34. Forced vital capacity (FVC) and diffusing capacity (DLCO) have improved from 91% to 97% and 70% to 85% predicted, respectively. The patient exhibited robust expansion of rese-cel that peaked at day 15 post-infusion (C max ) and was undetectable by day 29. The SSc patient’s drug product consisted of CAR T cells that were predominantly CD4+ prior to infusion and exhibited a mainly CD8+ phenotype at C max . Serum IFN-γ levels peaked at day 8, prior to rese-cel C max , and IL-6 peaked in parallel with C max . Peripheral B-cells were rapidly reduced following infusion and were undetectable by 15 days post-infusion. B-cell reconstitution was observed at 2 months post-infusion with reemergent B-cells presenting with a transitional (CD19+CD20+CD38++CD24++) naïve phenotype. In addition to peripheral depletion of B-cells, the patient exhibited depletion of B-cells in lymphoid tissue obtained from ultrasound guided left inguinal lymph node core needle biopsies. Lymphoid cells were characterized at both baseline and 21 days post-infusion utilizing immunohistochemical stains. A mixture of CD3 + T cells, CD19 + and CD20 + B-cells were observed in the baseline biopsy. At 21 days post-infusion, lymph node sections contained CD3 + T-cells and were devoid of CD19 + and CD20 + , expressing B-cells (Figure 1).
Conclusion: Data from the first SSc patient with significant skin involvement and disability dosed with rese-cel demonstrates early immunosuppressive-free clinical response and favorable 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 while off all immunosuppressive therapies. Additional patients undergoing rese-cel infusion in early 2025 will be presented at the EULAR meeting.
REFERENCES: NIL.
Acknowledgements: NIL.
Disclosure of Interests: Dinesh Khanna Abbvie, Bristol Myers Squibb, Astra Zeneca, Fate Therapeutics, Nkarta, Novartis, Monalisa Ghosh BMS, Cabaletta Bio, Bristol Myers Squibb, Cabaletta Bio, Kite, Novartis, Miltenyi, Fate Therapeutics, Ankoor Shah: None declared, Pei-Suen Eliza Tsou: None declared, Charles Ross: None declared, Courtney Little Cabaletta Bio, Carl DiCasoli Cabaletta Bio, Mikaela Raymond Cabaletta Bio, Jenell Volkov Cabaletta Bio, Daniel Nunez Cabaletta Bio, Thomas Furmanak Cabaletta Bio, Jason Stadanlick Cabaletta Bio, Larissa Ishikawa Cabaletta Bio, Zachary Vorndran Cabaletta Bio, Alexandra Ellis Cabaletta Bio, Jazmean Williams Cabaletta Bio, Steve Flanagan Cabaletta Bio, Quynh Lam Cabaletta Bio, Domenick Braccia Cabaletta Bio, Fatemeh Hadi Nezhad Cabaletta Bio, Raj Tummala Cabaletta Bio, Samik Basu Cabaletta Bio, David Chang Cabaletta Bio.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (