POS0656 TOLERABILITY AND EFFICACY OF BMS-986353 (CC-97540), A CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY MANUFACTURED USING A NEXT-GENERATION PROCESS FOR SYSTEMIC SCLEROSIS: UPDATED DATA FROM THE PHASE 1 BREAKFREE-1 STUDY

Abstract

Background:

In autoimmune diseases there is an unmet need for safe and effective treatments that will minimize or eliminate disease activity, prevent end-organ damage, and lower long-term treatment-related morbidity and mortality. A single infusion of CD19-directed autologous CAR T cells has been shown to induce durable, treatment-free remission or arrest of progression in multiple autoimmune diseases, including systemic sclerosis (SSc). BMS-986353 (CC-97540) is an investigational CD19 NEX-T® CAR T cell therapy that uses the construct of lisocabtagene maraleucel (liso-cel), which is indicated for B-cell lymphoma, and is manufactured via the NEX-T process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Preliminary data from the phase 1, multicenter, open-label Breakfree-1 trial (NCT05869955) in patients with severe refractory systemic lupus erythematosus, inflammatory myopathies, and SSc showed potentially transformational clinical responses, robust CAR T cell expansion, immune reset potential, and a manageable safety profile for BMS-986353 (Schett ACR 2024. Presentation 1753). Here, we report updated data on BMS-986353 in the SSc cohort.

Objectives:

To evaluate the tolerability and preliminary efficacy of BMS-986353 in patients with SSc.

Methods:

BMS-986353 CAR T cells were manufactured using the NEX-T process. Two to 9 days after lymphodepletion (3 days of fludarabine [30 mg/m²/day] and cyclophosphamide [300 mg/m²/day]), a single infusion of BMS-986353 was administered. Patients were treated with 10 × 10⁶ (dose level [DL] 1) or 25 × 10⁶ (DL2) CAR+ T cells. Pharmacokinetics were evaluated using droplet digital polymerase chain reaction to detect transgene copy numbers, and pharmacodynamics were assessed using flow cytometry.

Results:

As of December 6, 2024, 5 patients with SSc (SSc DL1, n=4; SSc DL2, n=1) were treated with BMS-986353. All treated patients in the SSc cohort were evaluable for safety and efficacy. In the SSc cohort, median age for DL1 was 51 years (range, 43–62); the DL2 patient was aged 41 years. Median follow-up was 106 days (range, 32–173) for DL1 and 46 days for the DL2 patient. Time from disease diagnosis to BMS-986353 infusion was a median of 1.5 years (range, 1.3–2.7) for DL1 and 3.1 years for the DL2 patient. DL1 patients received a median of 3.0 prior therapies (range, 2.0–5.0) and the DL2 patient received 3.0 prior therapies. At baseline, DL1 patients had a median Physician's Global Assessment score of 6.5 (range, 6.0–8.0), a median Health Assessment Questionnaire–Disability Index score of 1.8 (range, 1.1–2.8), and median total modified Rodnan skin score (mRSS) of 24.5 (range, 4.0–42.0); scores for the DL2 patient were 4.0, not available, and 7.0, respectively. Three DL1 patients had interstitial lung disease (ILD; 2 diffuse, 1 limited); the DL2 patient had limited disease with ILD. All 5 patients with SSc had treatment-emergent adverse events (TEAEs); 1 patient (DL1) had grade 3/4 TEAE related to BMS-986353 (grade 3 headache). One patient (DL1) experienced a hematologic TEAE (grade 1 neutropenia). Three patients (DL1) experienced cytokine release syndrome (CRS; all grade 1/2; median duration, 2.0 days; Table 1). One patient with SSc (DL1) had grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS; duration, 3.0 days; Table 1). There were no prolonged grade ≥3 cytopenias, systemic infections, or dose-limiting toxicities reported. Among DL1 patients, 3 patients had diffuse cutaneous SSc and demonstrated mRSS reduction as of the most recent evaluable follow-up of 15, 13, and 0 (with limited follow-up of 29 days post-infusion) points (Figure 1). Patients with SSc who received DL1 showed complete B-cell depletion and overall consistent, robust transgene expansion compared with patients with diffuse large B-cell lymphoma treated with liso-cel (TRANSFORM, NCT03575351) at the recommended phase 2 dose (RP2D; 100 x 10⁶ CAR+ T cells).

Conclusion:

BMS-986353, an investigational CD19-directed CAR T cell therapy using the construct of the FDA-approved liso-cel, is manufactured via the NEX-T process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. In patients with severe refractory SSc treated with BMS-986353, all CRS events observed were grade 1/2, brief, and reversible, and 1 patient experienced a grade 1 ICANS event, which resolved quickly. Preliminary data suggest promising efficacy in patients with SSc. The trial continues to enroll patients in all cohorts and dose escalation is ongoing to determine RP2D with optimal toxicity and efficacy profile by indication. Four patients are pending infusion and additional patients are scheduled for apheresis. Updated safety, efficacy, and translational data will be presented.

REFERENCES:

NIL. Table 1CRS and ICANS events in patients with SSc by dose level.DL1 (n=4)DL2 (n=1)CRSICANSCRSICANSMaximum grade, n (%)Grade 12 (50.0)1 (25.0)00Grade 21 (25.0)000Grade 30000Grade 4/50000Median onset (range), days7.0 (3–8)10.0 (10–10)——Median duration^a (range), days2.0 (2–2)3.0 (3–3)——Treatments, n (%)Tocilizumab2 (50.0)0——Dexamethasone01 (25.0)——a Multiple events occurring within 7 days of each other are considered as 1 episode.

Acknowledgements:

This study was funded by Bristol Myers Squibb. Professional medical writing and editorial assistance were provided by Richard Sora, PhD, of Caudex, a division of IPG Health Medical Communications, and were funded by Bristol Myers Squibb.

Disclosure of Interests:

Dinesh Khanna Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, Fate Therapeutics, Nkarta, Novartis, AstraZeneca, Margrit Wiesendanger: None declared, Richard Nash: None declared, Philip J. Mease AbbVie, Amgen, Eli Lilly, Johnson&Johnson, Novartis, Pfizer, UCB Data Safety Board only: Genascence, AbbVie, Acelyrin, Amgen, BMS, Century, Cullinan Biotech, Eli Lilly, Inmagene, Johnson&Johnson, Moonlake, Novartis, Pfizer, Takeda, UCB, AbbVie, Acelyrin, Amgen, BMS, Eli Lilly, Johnson&Johnson, Novartis, Pfizer, UCB, Anca Askanase AbbVie, Amgen, AstraZeneca, Aurinia, Biogen, BMS, Cabaletta, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, NKARTA, Pfizer, Sana, Sanofi, and UCB, AstraZeneca, BMS, Cabaletta, Idorsia, Genentech, NKARTA, Sana, Sanofi, and UCB, Elana Bernstein Boehringer Ingelheim, Synthekine, Neil Kramer AstraZeneca and GlaxoSmithKline, Amgen, Becton Dickenson, Johnson &Johnson, Immunic, Pfizer, Protagonist Therapeutics, Stryker, Bristol Myers Squibb, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Vikas Majithia Novartis, Kyverna, BMS, Cabaletta, Novartis: all paid to the institution, Jacques Azzi: None declared, David Korman: None declared, Krish Patel BMS, Kite, AbbVie, Adaptive, ADC Therapeutics, AstraZeneca, Beigene, BMS, Caribou, Genentech, Loxo/Lilly, Merck, Nurix, Pfizer, Pharmacyclics/Janssen, Sana, AbbVie, AstraZeneca, Adaptive, Adicet, BMS, CRISPR Therapeutics, Curis, Fate, Genentech/Roche, Kite, Loxo/Lilly, MEI, Merck, Nurix, Pfizer, Sana, Pharmacyclics/Janssen, Xencor, Matthew H. Schwede: None declared, Ran Reshef Allogene, Gilead Sciences, Incyte, TScan, Orca Bio, Pierre Fabre Pharmaceuticals, CareDx, Quell Biotherapeutics, Sana Biotechnology, Sail Biomedicines, Autolus, Bayer, Atara Biotherapeutics, Incyte, Sanofi, Immatics, AbbVie, Takeda, Gilead Sciences, CareDx, TScan, Cabaletta, Synthekine, BMS, J&J, Allogene, Genentech, Vittoria Therapeutics, Imugene, Ernesto Ayala: None declared, Alisha Desai Bristol Myers Squibb, Bristol Myers Squibb (Present), HUTCHMED (end Feb 2024), Griff McTume Bristol Myers Squibb, Sharmila Das Bristol Myers Squibb, Bristol Myers Squibb, Deciphera Pharmaceuticals, Jerill Thorpe Bristol Myers Squibb, Bristol Myers Squibb, Giuseppina Stifano Bristol Myers Squibb, Bristol Myers Squibb, Ashley Koegel Bristol Myers Squibb, Bristol Myers Squibb, Georg Schett BMS, Cabaletta, Johnson & Johnson, Kyverna, Novartis, BMS, Cabaletta, Eli Lilly, Johnson & Johnson, Miltenyi, Kyverna, Novartis, UCB. © 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.