Enhancing Immunotherapy Efficacy Through EZH2 Inhibitors
An innovative class of anticancer agents known as EZH2 inhibitors has shown promise in significantly boosting the effectiveness of certain cancer immunotherapies, according to a preclinical investigation conducted by researchers at Weill Cornell Medicine. The findings, detailed in a recent publication in Cancer Cell, indicate that the combination of EZH2 inhibition and T-cell-based immunotherapy is more effective in reducing non-Hodgkin B-cell lymphomas than immunotherapy alone.
The EZH2 enzyme, which is often active in tumor cells, plays a critical role in numerous cancer types. The study's authors suggest that targeting this enzyme can enhance both the potency and the longevity of immunotherapy responses. Dr. Wendy Béguelin, a prominent researcher in the field, noted that these promising preclinical results have led to the initiation of pilot studies involving EZH2 inhibitors combined with immunotherapies in patients diagnosed with lymphoma.
T-cell-based immunotherapies, such as CAR-T cell therapy, have been shown to effectively diminish or eradicate cancer symptoms in some patients with lymphomas and other blood-related cancers. However, in many cases, the cancer tends to reappear after treatment. This study posits that the inhibition of EZH2 may serve to augment the effectiveness and durability of these therapies.
EZH2 functions as an enzyme that regulates cell behavior by controlling gene expression. Mutations in the EZH2 gene are frequently found in lymphomas and are associated with a more aggressive cancer phenotype. Interestingly, research has indicated that inhibiting EZH2 could benefit patients even in instances where the EZH2 is non-mutant.
The U.S. Food and Drug Administration (FDA) approved an EZH2 inhibitor known as tazemetostat in 2020 for patients with relapsed follicular lymphoma that has not responded to standard treatments. Following this, Japan approved another EZH2 inhibitor, valemetostat, in 2022 for adult patients with refractory T-cell leukemia/lymphoma.
Research led by Dr. Béguelin and her team has uncovered that EZH2 activity can render lymphoma cells less detectable by the immune system while fostering an immunosuppressive environment around these tumors. By inhibiting EZH2, it is believed that this immunosuppressive effect can be reversed, thereby enhancing the efficacy of both patients' native anticancer T cells and T-cell immunotherapies.
To investigate this hypothesis, Dr. Béguelin and her colleagues developed a novel mouse model for follicular lymphoma, as well as a tumor line for the more prevalent and aggressive diffuse large B-cell lymphoma. The researchers then analyzed the changes in these lymphomas during treatment with EZH2 inhibitors in conjunction with two forms of T-cell immunotherapy: CAR-T cell therapy and a bispecific antibody therapy that engages lymphoma cells with the patient's own T cells.
The results revealed that EZH2 inhibition alone enhanced the cytotoxic activity of T cells against lymphoma cells. Notably, when mice were pretreated with the EZH2 inhibitor prior to CAR-T cell therapy, 100% of the subjects survived throughout a 40-day observation period, in stark contrast to the majority that succumbed within 11 days following CAR-T treatment without EZH2 inhibition. Similar survival rates were observed with valemetostat combined with CAR-T therapy.
Moreover, the combination of EZH2 inhibition and bispecific antibody therapy also led to significantly improved survival outcomes compared to bispecific antibody treatment alone. The researchers identified that the enhanced effectiveness of these immunotherapies stems not only from increased visibility of lymphoma cells but also from several additional mechanisms, including the reduction of immunosuppressive regulatory T cells and the reprogramming of anticancer T cells to enhance their functional longevity.
In addition to their ongoing clinical trials, the research team continues to investigate the underlying mechanisms through which EZH2 inhibition amplifies anticancer T-cell activity. This work could pave the way for more precise therapeutic targets in the future.
