New anticancer drugs could significantly improve immunotherapy

T cell-based immunotherapies, including CAR-T cell therapies, have significantly advanced treatment options for lymphomas such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Despite these advancements, predicting patient responses and understanding therapy resistance remain major challenges.

Recent research has shed light on how EZH2 inhibitors, a class of anticancer drugs, can enhance these therapies' effectiveness, potentially transforming lymphoma treatment.

EZH2, an enzyme crucial for regulating gene expression, often becomes overactive in lymphoma cells due to genetic mutations. This hyperactivity suppresses the immune system’s ability to recognize and attack tumors. Inhibiting EZH2 can reverse this immunosuppression, making tumor cells more vulnerable to immune attacks.

Researchers from Weill Cornell Medicine have demonstrated that combining EZH2 inhibitors with T cell-based immunotherapies not only enhances the immune response but also prolongs its durability.

The study, led by Dr. Wendy Béguelin, was published in Cancer Cell. Using newly developed preclinical models, researchers examined the effects of EZH2 inhibitors on both lymphoma cells and T-cell-based therapies. These models accurately replicated the genetic, epigenetic, and immunological characteristics of human DLBCL and FL, allowing for comprehensive analysis.

Dr. Yusuke Isshiki, a postdoctoral fellow and the study's first author, highlighted that this approach enabled the team to observe how EZH2 inhibition reprogrammed tumor environments and improved immunotherapy outcomes.

One significant finding was the impact of EZH2 inhibitors on CAR-T cell therapy. CAR-T cells are engineered T cells designed to target and kill cancer cells. In experiments using the EZH2 inhibitor tazemetostat combined with CAR-T cells, 100% of treated mice survived beyond the 40-day study period.

In contrast, mice receiving CAR-T therapy alone succumbed to the disease within 11 days. Similar results were observed with another EZH2 inhibitor, valemetostat, underscoring the drugs' potential to significantly boost CAR-T cell efficacy.

These inhibitors work through multiple mechanisms. They not only make lymphoma cells more recognizable to T cells but also reduce regulatory T cells, which typically suppress immune responses. Additionally, EZH2 inhibitors reprogram CAR-T cells to adopt a memory-like phenotype, enhancing their longevity and effectiveness.

Two-photon intravital imaging further revealed increased CAR-T cell recruitment and interaction within tumors when EZH2 inhibitors were used, resulting in more efficient lymphoma cell destruction.

Beyond CAR-T cells, EZH2 inhibition also improved the outcomes of bispecific antibody therapies. These therapies link a patient’s T cells directly to lymphoma cells, promoting targeted destruction. When combined with EZH2 inhibitors, bispecific antibodies achieved significantly better survival rates in preclinical models compared to antibody therapy alone.

The implications of these findings are profound. EZH2 inhibitors, such as tazemetostat and valemetostat, have already been approved for certain lymphoma treatments.

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.

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.

Dr. Béguelin expressed optimism about the potential of these combinations, stating, "These encouraging preclinical results have prompted us to initiate pilot studies of an EZH2 inhibitor with immunotherapies in lymphoma patients."

The study also highlights the broader potential of EZH2 inhibitors in oncology. By reprogramming immune responses and reducing tumor-induced immunosuppression, these drugs could enhance other immunotherapeutic approaches.

Future research will focus on understanding the precise mechanisms by which EZH2 inhibition boosts T cell function, potentially leading to even more targeted therapies.

Incorporating EZH2 inhibitors into immunotherapy regimens could mark a turning point in the fight against lymphomas.

As researchers continue to uncover the enzyme’s role in immune regulation, patients stand to benefit from treatments that are not only more effective but also more enduring.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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