Reversing T Cell Exhaustion Improves Effectiveness of Myeloma Immunotherapies
Two companion papers in Blood highlight how mezigdomide may enhance CAR-T and bispecific antibody treatments
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.”
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.”
The research was conducted in collaboration with investigators from Bristol Myers Squibb, the University of Oxford, and the University of Navarra in Spain. Funding support was provided by the International Myeloma Society Career Development Award, the Paula and Rodger Riney Foundation, the CRUK Cancer Sciences DPhil Programme, Bristol Myers Squibb, and the National Cancer Institute.
Links to the studies:
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 47,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and leading schools of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care from conception through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes more than 6,400 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals,” “Best in State Hospitals,” “World’s Best Hospitals,” and “Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2025-2026.
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