Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of BMS-986353 (CC-97540), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy Manufactured Using a Next-Generation Process, for Severe, Refractory Autoimmune Diseases: Updated Data from Ongoing Phase 1, Multicenter, Open-Label Studies

Introduction

CD19 CAR T cell therapies are highly effective for several aggressive B-cell malignancies. Emerging data suggest that these therapies may lead to durable, treatment-free responses in multiple autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIMs), systemic sclerosis (SSc), and multiple sclerosis (MS). BMS-986353 (CC-97540) is an investigational CAR T cell therapy expressing the CD19-targeting CAR used in FDA-approved lisocabtagene maraleucel (liso-cel). BMS-986353 is manufactured using the NEX-T^TM process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Here, we report updated data on BMS-986353 in severe, refractory autoimmune diseases.

Methods

Two phase 1, multicenter, open-label studies are investigating BMS-986353 in patients (pts) with severe, refractory SLE, IIM, and SSc (CA061-1001; NCT05869955), and relapsing or progressive forms of MS (CA061-1006; NCT06220201). CAR T cells were manufactured using the NEX-T process and autoimmune-directed therapies were tapered before BMS-986353 infusion. Two to 9 d after lymphodepletion (3 d of fludarabine [30 mg/m²/d], cyclophosphamide [300 mg/m²/d]), a single infusion of BMS-986353 was administered. Pts were treated with 5 × 10⁶ (MS only), 10 × 10⁶, or 25 × 10⁶ CAR+ T cells according to dose level. Pharmacokinetics were evaluated using droplet digital PCR to detect transgene copy numbers, and pharmacodynamics were measured using flow cytometry.

Results

As of Jul 12, 2024, 7 pts were treated with BMS-986353 (SLE, n=5; SSc, n=1; relapsing-remitting MS [RRMS], n=1). Seven pts were evaluable for safety; 4 pts were evaluable for efficacy (median follow-up of 167.5 d [range, 68-240]). All 5 pts with SLE had history of renal organ system involvement (BILAG category A) and disease refractory to multiple prior therapies (range 5-8); at screening, scores were (median [range]): SLE Disease Activity Index 2000 (SLEDAI-2K), 12.0 (7.0-22.0); Physician's Global Assessment (PGA), 2.3 (1.5-2.5). The pt with SSc was aged 43 y, and had history of progression of diffuse cutaneous SSc after 2 therapies and a modified Rodnan skin score of 18; the pt with RRMS was aged 33 y, and had history of active clinical disease despite 3 prior anti-CD20 therapies and an Expanded Disability Status Scale score of 3.0. Cytokine release syndrome was reported in 1 pt with SLE (grade [gr] 1) and 1 pt with SSc (gr 2), both resolved within 1 d. ICANS was reported in 1 pt with SSc (gr 1) and resolved in 1 d. Gr 3/4 transient lymphodepletion-related cytopenia occurred in 4 pts with SLE and 1 pt with MS. There were no prolonged gr ≥3 cytopenias or dose-limiting toxicities reported.

In all efficacy evaluable pts, significant improvements in SLEDAI-2K (median, 4.0) and PGA (median, 0.55) were observed. dsDNA seroconverted and complements normalized for all pts who had abnormal values at screening. All pts remain off autoimmune-directed therapies without evidence of disease flare.

Pts with SLE treated with 10 x 10⁶ CAR+ T cell dose of BMS-986353 showed complete B-cell depletion and similar robust cellular expansion compared with pts 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). At the time of B-cell reconstitution following BMS-986353, re-emerging B cells were predominantly naive.

Conclusions

BMS-986353, a NEX-T investigational CD19-targeted CAR T cell therapy, has a more rapid manufacturing time and optimized phenotypic attributes. In pts with severe, refractory autoimmune diseases, BMS-986353 demonstrates a low rate of low gr CRS and ICANS events. Preliminary data suggest promising efficacy in pts with SLE despite discontinuation of all lupus therapies. Robust CAR T cell expansion comparable to the RP2D of liso-cel and complete B-cell depletion were observed after BMS-986353 at a dose of 10 x 10⁶ CAR+ T cells despite being 1/10 of the RP2D of liso-cel. The studies continue to enroll pts in all autoimmune indications. Updated safety, efficacy, and translational data will be presented.

Mueller:Sobi, Abbvie, Beigene: Honoraria, Speakers Bureau; ArgoBio, CRISPRTherapeutics: Consultancy; Kite/Gilead; Astrazeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Miltenyi, BMS, Janssen, Novartis: Consultancy, Honoraria, Speakers Bureau. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy; BMS: Consultancy, Research Funding, Speakers Bureau; Caribou: Consultancy; Fate Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Loxo: Consultancy, Research Funding; Nurix: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sana: Consultancy; Xencor: Consultancy, Research Funding; Century: Research Funding; CRISPR: Research Funding; Curis: Research Funding; Pharmacyclics: Research Funding. Reshef:Cabaletta: Research Funding; Orca Bio: Consultancy; Gilead Sciences: Consultancy, Research Funding; Sanofi: Research Funding; Precision Biosciences: Research Funding; Autolus: Consultancy; Synthekine: Research Funding; Incyte: Consultancy, Research Funding; CareDx: Research Funding; Immatics: Research Funding; BMS: Research Funding; J&J: Research Funding; Bayer: Consultancy; Atara Biotherapeutics: Research Funding; Genentech: Research Funding; Sana Biotechnology: Consultancy; TCR2: Research Funding; TScan: Consultancy, Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Quell Biotherapeutics: Consultancy; Allogene: Consultancy. Cherry:Sanofi: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Dava Oncology: Honoraria. Vandenberghe:Novartis: Consultancy; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Medialis Limited: Consultancy; Bristol Myers Squibb: Consultancy. Houot:Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche, Abbvie: Honoraria; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Incyte, Miltenyi, Roche, Abbvie: Consultancy. von Tresckow:AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis: Other: Travel and congress support ; Esteve (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), and Takeda (Inst): Research Funding; AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche and Takeda: Honoraria; Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi and Takeda: Consultancy. Stifano:Bristol Myers Squibb: Current holder of stock options in a privately-held company. Koegel:Bristol Myers Squibb: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: Patents. Falcon:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Chaudhry:Bristol Myers Squibb: Current Employment. Kelly:Bristol Myers Squibb: Current Employment. Thorpe:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Frisbee:Bristol Myers Squibb: Current Employment. Charab:Bristol Myers Squibb: Current Employment. Das:Bristol Myers Squibb: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ly:Bristol Myers Squibb: Current Employment. Ogasawara:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Caimi:Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Sobi: Consultancy; Synthekine: Membership on an entity's Board of Directors or advisory committees; Arvinas: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy.