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2088 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

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Autoimmune disorders, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Immune Disorders, Treatment Considerations, Biological therapies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Fabian Mueller, MD1, Krish Patel, MD2*, Ran Reshef, MD, MSc3, Mohamad Cherry, MD, MSc4, Richard Nash, MD5*, Ernesto Ayala, MD6, Jingmei Hsu, MD, PhD7, Jacques Azzi8*, Peter Vandenberghe, MD, PhD9, Roch Houot, MD, PhD10*, Bastian von Tresckow11, Giuseppina Stifano12*, Ashley Koegel, MD13, Susana Falcon13*, Burhan Chaudhry13*, Lisa Kelly13*, Jerill Thorpe14*, Alyse Frisbee14*, Sam Charab14*, Sharmila Das13*, Thomas Ly15*, Ken Ogasawara, PhD, MPH13* and Paolo Caimi16*

1Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
2Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute, Seattle, WA
3Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY
4Atlantic Health System, Morristown, NJ
5Health One Cares, Denver, CO
6Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
7NYU Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY
8Icahn School of Medicine at Mount Sinai, New York, NY
9University Hospitals Leuven, Leuven, Belgium
10University Hospital CHU de Rennes, Rennes, France
11Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
12Bristol Myers Squibb, Cambridge, MA
13Bristol Myers Squibb, Princeton, NJ
14Bristol Myers Squibb, Seattle, WA
15Bristol Myers Squibb, San Diego, CA
16Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

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-TTM 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 x 106 (MS only), 10 x 106, or 25 x 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.

Disclosures: 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.

*signifies non-member of ASH