Researchers at Weill Cornell Medicine have discovered that EZH2 inhibitors, a class of anticancer drugs, can significantly enhance the effectiveness of T-cell-based immunotherapies in treating B-cell non-Hodgkin lymphomas (B-NHL). The preclinical study, published in Cancer Cell, demonstrates that combining EZH2 inhibition with immunotherapies improves tumor recognition and elimination, potentially overcoming resistance and improving patient outcomes. These encouraging results have led to the initiation of pilot clinical studies to evaluate this combined approach in lymphoma patients.
EZH2 Inhibition Enhances Immunotherapy
EZH2 is an enzyme that regulates gene expression, and its hyperactivity is common in lymphomas, suppressing the immune system's ability to attack tumors. Inhibiting EZH2 can reverse this immunosuppression, making tumor cells more vulnerable. The study found that EZH2 inhibitors not only make lymphoma cells more recognizable to T cells but also reduce regulatory T cells, which typically suppress immune responses. This reprogramming of the tumor microenvironment leads to enhanced and more durable immune responses.
Dr. Wendy Béguelin, the John P. Leonard, MD/Gwirtzman Family Research Scholar in Lymphoma and an assistant professor of pharmacology in medicine at Weill Cornell Medicine, noted, "These encouraging preclinical results have prompted us to initiate pilot studies of an EZH2 inhibitor with immunotherapies in lymphoma patients."
Synergistic Effects with CAR-T Cell Therapy and Bispecific Antibodies
The research team, led by Dr. Yusuke Isshiki, utilized preclinical models that accurately replicated the genetic, epigenetic, and immunological characteristics of human diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In experiments combining the EZH2 inhibitor tazemetostat with CAR-T cells, 100% of treated mice survived beyond the 40-day study period, whereas mice receiving CAR-T therapy alone succumbed to the disease within 11 days. Similar results were observed with valemetostat, another EZH2 inhibitor.
Furthermore, EZH2 inhibition also improved the outcomes of bispecific antibody therapies, which link a patient’s T cells directly to lymphoma cells. When combined with EZH2 inhibitors, bispecific antibodies achieved significantly better survival rates in preclinical models compared to antibody therapy alone.
Mechanisms of Action and Clinical Implications
The study revealed that EZH2 inhibitors work through multiple mechanisms. They reprogram CAR-T cells to adopt a memory-like phenotype, enhancing their longevity and effectiveness. Two-photon intravital imaging further showed increased CAR-T cell recruitment and interaction within tumors when EZH2 inhibitors were used, resulting in more efficient lymphoma cell destruction.
Tazemetostat received FDA approval in 2020 for relapsed or refractory FL, while valemetostat was approved in Japan in 2022 for adult T-cell leukemia/lymphoma. The current research suggests that incorporating these inhibitors into broader immunotherapy regimens could amplify their benefits.
Ongoing Clinical Trials
Clinical trials are now underway to evaluate this combined approach in patients. Two trials, NCT05934838 and NCT05994235, aim to assess the safety and efficacy of EZH2 inhibitors with immunotherapies for B-cell lymphomas. These trials are investigating the combination of tazemetostat with standard-of-care CAR-T therapy in relapsed or refractory B-NHL and with mosunetuzumab in untreated FL.
The findings highlight the potential of EZH2 inhibitors in oncology, as they could enhance other immunotherapeutic approaches by reprogramming immune responses and reducing tumor-induced immunosuppression. Future research will focus on understanding the precise mechanisms by which EZH2 inhibition boosts T cell function, potentially leading to even more targeted therapies.
