BMS-986458, a first-in-class, highly selective, and potent ligand-directed degrader (LDD) of B-cell lymphoma 6 (BCL6) combined with T-cell engagers (TCEs) demonstrates preclinical synergistic antitumor efficacy for the treatment of B-cell non-Hodgkin lymphoma (NHL)

Abstract

Abstract Introduction: BCL6 is a transcriptional repressor required for normal B-cell maturation. BCL6 is one of the most frequently genetically misregulated proteins in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) leading to repressed apoptosis and increased proliferation. BMS-986458 is an oral, highly selective bifunctional cereblon-dependent LDD of BCL6. BMS-986458 has shown promising preliminary efficacy and acceptable tolerability in heavily pre-treated patients with relapsed/refractory DLBCL and FL in an ongoing phase 1/2 trial (NCT06090539). Preclinically, in the majority of BCL6-expressing NHL models, BMS-986458 potently and rapidly degrades BCL6, leading to antitumor efficacy. Furthermore, immunomodulatory properties together with enhanced CD20 transcription and protein levels, surface expression, and receptor clustering in selected models may contribute to the anti-tumor response and combinatorial potential. Herein, we describe synergy of BMS-896458 combined with TCEs. Methods: In vitro:DLBCL models were pre-treated with BMS-986458 for 72h prior to co-culture with T cells isolated from healthy donors (n=3). TCEs were added and cell viability assessed by flow cytometry after 3 days. DLBCL models were chosen based on basal CD20 expression, BMS-986458 response, and BCL6-degradation–dependent CD20 induction. In vivo: A humanized mouse model was established by inoculating OCI-LY-1 DLBCL CDX tumor-bearing hCRBN NSG mice with hPMBCs (25×106 cells/ml). 3 days after hPBMC injection, mice were randomized in 4 groups (8–9 per group): vehicle, BMS-986458 (5 mg/kg BID PO), glofitamab (glofit; 1 µg/mouse IV QW), and combination (BMS-986458+glofit). Tumor size was measured every 3-4 days and hPBMC engraftment and cytokine analyses performed at study end. Tumor immune infiltrate was evaluated using immunohistochemistry (IHC) on a satellite cohort following 2 wks of treatment. Results: In vitro anti-tumor response to BMS-986458 + 3 CD20xCD3 TCEs (glofit, epcoritamab, and mosunetuzumab) was evaluated in 3 cell lines. HT cells had the highest synergistic response due to the largest CD20 fold-induction from baseline. Responses were milder in RIVA cells due to higher CD20 baseline expression and smaller fold-change following treatment. WILL-2 cells, a BCL6-negative activated B-cell model with low baseline CD20, had very mild anti-tumor response and combo synergy. BMS-986458+TCE did not significantly impact CD4+/CD8+ T-cell viability or expression of activation markers CD25, CD69, and HLD-DR vs TCE alone. In hDLBCL mouse xenografts, BMS-986458 and glofit monotherapy led to 59% and 75% tumor volume reductions (TVR) vs vehicle, respectively. Synergistic tumor inhibition, with 6/8 tumor-free mice and overall 97% TVR, was seen with BMS-986458+glofit. The combo was well tolerated, with no significant body weight loss. At study end, peripheral blood samples showed increased T-cell expansion and CD8/CD4 ratio with combo vs monotherapy. HLA-DR expression on CD8 T cells was significantly reduced in glofit monotherapy and combo groups. No changes in HLA-DR expression occurred with BMS-986458 alone vs vehicle. Human cytokine (IFN-γ, GM-CSF, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12p70, and IL-10) levels were measured in mouse plasma on Day 36 and no significant changes were observed with BMS-986458±glofit; however, treatment with glofit alone significantly enhanced IFN-γ (P<0.01), GM-CSF (P<0.01), and TNF-α (P<0.05) vs vehicle. IHC showed a modest increase in CD3+ cells, predominantly at the tumor's edge, in single-agent BMS-986458 and glofit-treated mice. Importantly, combo treatment resulted in a significant increase in CD3+ cells tumor infiltration vs other groups. Conclusions: Combining BMS-986458 with TCEs results in synergistic T cell-driven tumor cell killing across multiple DLBCL models. In vivo, using a hPBMC mouse DLBCL model, BMS-986458+glofit demonstrated synergistic antitumor efficacy, and increased infiltration of CD3 T cells into the tumor microenvironment. No evidence of T-cell activation based on HLA-DR expression or plasma-measured cytokines was observed with BMS-986458±glofit. In vitro studies showed synergy was observed irrespective of CD20 fold-induction following BMS-986458 treatment, and was also observed in models lacking BCL6 expression, indicating that additional immune mechanisms may be contributing to the antitumor activity beyond direct cytotoxic tumor intrinsic effects.