Type: Oral
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Novel Therapeutic Approaches in Lymphoma
Hematology Disease Topics & Pathways:
Research, Fundamental Science
In vitro, BMS-986458 rapidly degrades BCL6 protein to levels that drive broad anti-tumor effects in 80% of BCL6 expressing NHL cell lines and all ex vivo patient derived xenograft (PDX) models evaluated. Extensive transcriptomic analysis shows the anti-tumor effect of BCL6 degradation is achieved through modulation of a regulon associated with cell-cycle checkpoints, anti-proliferative signaling and interferon response pathways. A novel component of the BCL6 regulon is repression of the highly efficacious therapeutic surface target CD20, whose downregulation is associated with relapsed/refractory (R/R) disease. Using BMS-986458, we demonstrate a broad enhancement of CD20 transcription, surface expression and clustering, increasing up to 20-fold within 72 hrs across multiple Diffuse Large B-cell Lymphoma (DLBCL) cell line models. This enhancement results in potent synergism of BMS-986458 with anti-CD20 agents from both cell intrinsic and ADCC-mediated anti-tumor mechanisms. The cell intrinsic anti-tumor impact of BCL6 degradation was confirmed in vivo using human cell line-derived xenograft (CDX) and PDX models of R/R DLBCL. In these studies, once daily oral dosing of BMS-986458, resulted in deep and sustained degradation of BCL6 leading to CDX tumor regression and significant survival benefit of PDX models. Furthermore, BMS-986458 in combination with anti-CD20, resulted in tumor regression and tumor free animals (<70%), without body weight loss. In additional studies, we demonstrate using both in vitro T-follicular helper cell (Tfh) differentiation assays and evaluation of immunocompetent mice, that BMS-986458 treatment phenotypically modulates lymph-resident Tfh populations without affecting cellular viability, highlighting the potential functional impact of BCL6 degradation on this pro-tumor immune compartment. Non-clinical safety evaluations show that in addition to the absence of impact on normal bone marrow populations in vitro, BMS-986458 is pharmacodynamically active and well tolerated in vivo following 28-day dog toxicity studies.
In summary, the robust cell intrinsic mechanism of BMS-986458 across BCL6-expressing NHL tumors together with its stimulation of CD20 surface expression and the immunomodulatory impact on Tfh populations, demonstrate that BCL6 degradation using BMS-986458 has the potential to be highly efficacious and represents a novel mechanism of action for NHL therapy. Collectively, this evidence supports its current clinical investigation as an orally dosed single agent or in combination with an anti-CD20 agent (NCT06090539), providing a potential first-in-class chemo-free therapeutic option for B-cell NHL patients.
Disclosures: Groocock: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Deb: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gamez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Castiglioni: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sanchez-Castillo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Schumacher: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rondan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jankeel: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Martinez-Garcia: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wood: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Christoforou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Guarinos: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Narla: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zapf: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Carrancio: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierce: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rolfe: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bence: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopez-Girona: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mortensen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.