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Golcadomide with CD20 T-cell engager extends survival in lymphoma model by boosting T-cell activation and trafficking

ABSTRACT: Despite recent clinical advances in the treatment of diffuse large B-cell lymphoma, relapsed/refractory patients remain an unmet medical need. Immune-based therapies, such as CAR T and T cell bispecific antibodies, redirect T-cells to target antigens expressed on the malignant cells, have demonstrated promising antitumor and clinical activity. However, even with these advanced therapies some patients do not have non-durable responses, potentially due to tumor microenvironment factors such as lack of T-cell infiltration. Golcadomide, a potential first-in-class Aiolos and Ikaros degrading CRBN E3 ligase modulator (CELMoD), has a multifaceted mechanism of action, including direct antitumor effects and T-cell activation. This study demonstrates that through specific degradation of transcription factors, Aiolos and Ikaros, golcadomide enhances T-cell function through increased proliferation and cytokine production. Spatial transcriptomic and multiplex immunofluorescence data revealed that single agent golcadomide treatment enhanced T-cell functions in a syngeneic GEMM lymphoma model, including T-cell activation and trafficking to the TME, suggesting potential synergy with T-cell engagers. In a combination with a CD20xCD3 murine surrogate T-cell engager, golcadomide increased T-cell mediated cytotoxicity against lymphoma cells and extended survival in an aggressive lymphoma GEMM compared to single-agent bispecific treatment. These findings support the clinical rationale for combining these immunotherapeutic modalities to improve outcomes in DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305825 | GEO | 2026/08/18

REPOSITORIES: GEO

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Discovery of golcadomide (CC-99282) as a promising drug candidate for diffuse large B-cell lymphoma (DLBCL)

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