Researchers Reverse Immune Cell Dysfunction by Degrading Key Gene Regulatory Proteins

Researchers at the Icahn School of Medicine at Mount Sinai, Bristol Myers Squibb, and the University of Oxford have discovered a way to give worn-out immune cells a second wind in the fight against multiple myeloma.

In two studies published this month in Blood, the Journal of the American Society of Hematology, (doi.org/10.1182/blood.2025030891 and 10.1182/blood.2025030873) they 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-tumor response.

"Our findings show that mezigdomide can reinvigorate exhausted T cells and enhance the activity of immunotherapies that are already changing the standard of care for multiple myeloma," said Samir Parekh, MD, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai and senior author of the studies.

This approach addresses one of the fundamental challenges in treating patients whose disease has returned after multiple lines of therapy."

Samir Parekh, MD, Professor, Medicine, Icahn School of Medicine at Mount Sinai 

In analyses of bone marrow samples from patients with relapsed multiple myeloma, the researchers found that treatment with mezigdomide significantly reduced populations of dysfunctional T cells expressing key exhaustion markers, which include PD-1 and TIGIT. At the same time, the drug enhanced the tumor-killing activity of both CAR-T cells and bispecific T cell engagers in preclinical models, leading to deeper tumor clearance and improved survival. The studies also uncover the biological mechanism behind these effects.

Mezigdomide works by targeting and degrading two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), which the researchers identified as central regulators of T cell dysfunction. Using advanced multi-omic approaches, including gene expression profiling and analysis of three-dimensional genome organization, the team showed that these proteins help sustain the genetic and epigenetic programs that keep T cells in an exhausted state.

"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, hematology clinician at Oxford University Hospitals NHS Foundation Trust and PhD candidate at the University of Oxford. "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."

"By removing these key regulators, mezigdomide effectively rewires the immune system," said Dr. Parekh. "It shifts T cells from a dysfunctional state to a more active, tumor-fighting state, allowing them to produce critical signaling molecules and mount a stronger response against cancer."

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.

"Progress for patients depends on advancing our understanding of both tumor-intrinsic and extrinsic factors of the disease biology. While there have been meaningful therapeutic advances for multiple myeloma patients, areas of unmet medical need still remain. Working closely with academic partners is essential to building the scientific foundation that informs future research, including the potential role of approaches such as targeted protein degradation," emphasizes Anita Gandhi, Vice President, Translational Development, Bristol Myers Squibb.

For patients, particularly those with relapsed disease who have limited treatment options, this strategy could represent a meaningful advance.

"Patients who have undergone multiple therapies often have a weakened immune system, which can limit how well newer treatments work," Dr. Parekh said. "Reversing T cell dysfunction has the potential to improve both the depth and durability of response."