Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, Bispecific Antibody Therapy, Non-Biological therapies, assays, Plasma Cell Disorders, Chemotherapy, Combination therapy, Diseases, immune mechanism, Therapies, Lymphoid Malignancies, Adverse Events, Biological Processes, Technology and Procedures
Methods: The inhibitory effects of CELMoD agents on stimulated cytokine release was investigated in healthy donor monocytes, macrophages, and peripheral blood mononuclear cells (PBMCs). Cells were pretreated overnight (~17 h) with clinically relevant concentrations of lenalidomide (LEN), pomalidomide (POM), iberdomide (IBER), mezigdomide (MEZI; BMS-986348; CC-92480), or dimethyl sulfoxide (DMSO), then stimulated with lipopolysaccharide (LPS) or anti-CD3/-CD28 beads to trigger cytokine release. Components of the in vitro model included: (a) PBMCs as a source of T and myeloid cells, (b) target human myelogenous leukemia cells (K562) engineered to overexpress BCMA or multiple myeloma (MM) cells with high endogenous BCMA expression (H929); BCMA-null K562 cells served as a control, and (c) ALNUC. The in vitro assay was performed by pretreating PBMCs overnight with CELMoD agents before the addition of target cells at a 1:5 target:effector ratio and ALNUC. Secreted cytokines were measured using the MSD® V-Plex® proinflammatory panel at various timepoints.
Results: Pretreatment of monocytes and macrophages with CELMoD agents inhibited LPS‑induced IL-6 secretion, with the greatest inhibition (up to 3-fold) reported with MEZI. Pretreated PBMCs also had reductions in LPS-induced IL-6, IL-1β, and TNFα secretion of up to 2-, 5- and 6-fold, respectively. In T-cells stimulated with anti-CD3/-CD28 beads, CELMoD agent pretreatment resulted in enhanced secretion of T-cell derived cytokines. Thus, CELMoD agents had differential impact on cytokines secreted by T cells vs myeloid cells.
In the in vitro assay, non-pretreated PBMCs in the presence of K562-BCMA cells and ALNUC secreted ≥ 800 pg/mL of IL-6 within 6 h of stimulation, demonstrating the robustness of the assay. In PBMCs pretreated with MEZI prior to co-culture with K562-BCMA cells, ALNUC-induced IL-6 secretion was suppressed by up to 50% and IL-1β secretion by up to 95% vs PBMCs pretreated with DMSO. Secretion of IL-2, TNFα, and IFNγ, critical cytokines related to T-cell lytic activity, was not suppressed in our model following MEZI pretreatment.
Conclusions: CELMoD agents can suppress secretion of the proinflammatory cytokines IL-6 and IL-1β by monocytes/macrophages and PBMCs in vitro, with the strongest suppression observed with MEZI. In an ex vivo co-culture system of PBMCs with BCMA-expressing target cells, pretreatment with MEZI suppressed ALNUC-induced secretion of IL-6 and IL-1β, but not secretion of T cell-mediated cytokines. Our data demonstrate strong reductions in proinflammatory myeloid cell-derived cytokines by CELMoD agents while maintaining these agents’ pro-immune properties, suggesting that potent CELMoD agents such as MEZI have the potential to mitigate CRS in patients with MM receiving TCEs.
Disclosures: Jeyaraju: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Methods of treating cytokine-related adverse events. Alapa: Bristol Myers Squibb: Current Employment. O’Donohue: Bristol Myers Squibb: Current Employment. La Motte-Mohs: Notch Therapeutics: Patents & Royalties: Patents; MacroGenics: Current equity holder in publicly-traded company, Patents & Royalties: Patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Boss: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Hagner: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pourdehnad: Bristol Myers Squibb: Current Employment, Patents & Royalties: Patents owned by BMS. Burgess: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Pierceall: Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Thakurta: Bristol Myers Squibb: Ended employment in the past 24 months; Berg Health: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees.
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