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In two studies published this month in Blood, the research team, including researchers from the MRC Weatherall Institute of Molecular Medicine, found that using the drug mezigdomide (a cereblon E3 ligase modulator developed by Bristol Myers Squibb) can help these cells regain their strength and better destroy cancer by restoring the immune system's ability to attack cancer and significantly improving the effectiveness of next-generation immunotherapies.
T cell-based therapies, including CAR-T cells and bispecific antibodies, have transformed outcomes for patients with multiple myeloma, a cancer of plasma cells in the bone marrow. However, many patients eventually relapse, in part because their T cells become "exhausted" and less capable of mounting an effective anti-tumour response.
In analyses of bone marrow samples from patients with relapsed multiple myeloma, the researchers found that treatment with mezigdomide significantly reduced the population of dysfunctional T cells expressing key exhaustion markers, including PD-1 and TIGIT. At the same time, the drug enhanced the tumour-killing activity of both CAR-T cells and bispecific T cell engagers in preclinical models, leading to deeper tumour clearance and improved survival. The studies also uncover the biological mechanism behind these effects.
"Whilst the effects of immunomodulatory imide drugs and cereblon E3 ligase modulators on myeloma cells are understood, it was really exciting to instead focus on how these drugs affect the surrounding immune cells," said first author Lucia Chen, haematology clinician at Oxford University Hospitals NHS Foundation Trust and PhD candidate in the Milne Group at the MRC WIMM.
"We found that they can reprogram nearby T cells into a more active, cancer-fighting state by removing key gene regulators Ikaros and Aiolos. The role of these gene regulatory factors in T cell dysfunction is understudied. Understanding these epigenetic pathways could have implications for immune therapies in myeloma and other cancers."
The findings provide a strong scientific rationale for combining mezigdomide with T cell-based therapies in clinical settings. Early-phase clinical trials evaluating these combinations are underway.
Read the full news story from Mount Sinai.
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