The results of a preclinical study by lymphoma researchers at Weill Cornell Medicine suggest that an emerging class of anticancer drugs called EZH2 inhibitors may greatly enhance the potency of some cancer immunotherapies.
EZH2 enzyme activity in tumor cells is recognized as a significant factor in many cancers. The newly reported study, including work in mouse models, found that combining T-cell-based immunotherapy with EZH2 inhibition was more effective at shrinking B-cell non-Hodgkin lymphomas (B-NHL) than immunotherapy alone.
“These encouraging preclinical results have prompted us to initiate pilot studies of an EZH2 inhibitor with immunotherapies in lymphoma patients,” said Wendy Béguelin, PhD, the John P. Leonard, MD/Gwirtzman Family Research Scholar in Lymphoma and an assistant professor of pharmacology in medicine at Weill Cornell Medicine.
Senior author Béguelin, together with colleagues including first author Yusuke Isshiki, PhD, a postdoctoral fellow in the laboratories of Béguelin and Ari Melnick, MD, the Laurel Gebroe Family Professor of Hematology/Oncology at Weill Cornell Medicine, reported their findings in Cancer Cell, in a paper titled, “EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.” In their paper, the team confirmed that their therapeutic approach is being evaluated in two clinical trials investigating immunotherapy outcomes in B-cell lymphoma patients.
T-cell-based immunotherapies, including CAR-T cells, have been effective at reducing or eliminating signs of cancer in some patients with lymphomas and other blood malignancies. In most cases, however, signs of cancer eventually return. “Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has transformed the treatment of refractory B-cell non-Hodgkin’s lymphomas (B-NHL), including diffuse large B cell lymphoma (DLBCL) and multiply relapsed follicular lymphoma (FL),” the team wrote. “However, only 30–40% of DLBCL and FL patients maintain durable complete remission after five years.”
EZH2 is an enzyme that normally helps program cell behavior by controlling the expression of specific genes. Mutations in the EZH2 gene, which makes the enzyme more active, are now recognized as common features of lymphomas, and inhibiting this enzyme has been found to benefit lymphoma patients even when they have non-mutant EZH2.
An EZH2 inhibitor called tazemetostat was approved by the FDA in 2020 for use in patients with follicular lymphoma that has relapsed or not responded to standard treatments. A second EZH2 inhibitor, valemetostat, was approved in Japan in 2022 for the treatment of patients with relapsed or refractory adult T-cell leukemia/lymphoma.
Research by Béguelin and others has shown that EZH2 activity makes lymphoma cells less visible to the immune system, and generally helps to create an immunosuppressive environment around lymphomas. “In established lymphomas, EZH2 promotes immune evasion by silencing major histocompatibility complex (MHC) expression, hindering tumor-T cell interactions,” the investigators wrote.
The newly reported study proposed that inhibiting EZH2 might help enhance the potency and durability of immunotherapies. “We hypothesized that EZH2 inhibitors can restore interactions of lymphoma B cells with T cells beyond MHC-dependent interactions, and that combining EZH2 inhibitors with T cell immunotherapies may enhance tumor recognition and elimination.”
Suitable preclinical animal models to test this hypothesis have not been available, so Béguelin and her colleagues started by developing a new mouse model for follicular lymphoma and a tumor line for the more common and aggressive diffuse large B-cell lymphoma. The researchers then detailed changes in these lymphomas during treatment with EZH2 inhibitors and/or two T-cell-based immunotherapies—one a CAR-T cell therapy and the other a bispecific antibody therapy (CD20xCD3) that binds lymphoma cells to the patients’ own T cells.
“Despite the different pathways for target recognition and engagement, both CD20xCD3 bispecific antibodies and CD19 CAR-T therapies ultimately rely on the activation of T cells to exert their anti-tumor effects,” the investigators noted. “… we evaluated the combination of EZH2 inhibitor tazemetostat with CD20xCD3 T cell engaging bispecific antibody or CD19 CAR-T cells (CAR-T19).”
The results showed that EZH2 inhibition on its own enhanced the killing of lymphoma cells by T cells, and that pretreatment with an EZH2 inhibitor could greatly improve the effectiveness of T-cell immunotherapies against these lymphomas. “We investigated EZH2 inhibition in combination with both therapies, showing its potential to reduce the immunosuppressive properties of the TME and improve T cell-mediated killing,” the researchers commented.”
![Pretreatment with EZH2 inhibitor (top right) leads to higher recruitment of CAR-T cells (red) into the lymph node tumor compared with control (top left). Pretreatment with EZH2 inhibitor (bottom right) also leads to closer contacts between lymphoma B cells and T cells in culture. [Courtesy of the Béguelin lab]](https://www.genengnews.com/wp-content/uploads/2024/12/Low-Res_Beguelin_Illustrative-Figure-CC2024_3-300x201.jpg)
In one experiment, treatment with tazemetostat plus CAR-T cells enabled 100% of mice to survive for the 40-day study period and beyond, whereas most died within 11 days after the same dose of CAR-T cell treatment alone. Results for valemetostat plus CAR-T treatment were similar. “This manuscript presents evidence that inhibiting EZH2 can overcome CAR-T therapy resistance by enhancing lymphoma immunogenicity, facilitating interaction between lymphoma B cells and T cells, and improving endogenous T cell and CAR-T cell functions,” the team stated.
EZH2 inhibition combined with bispecific antibody treatment also greatly boosted survival compared with bispecific antibody treatment alone. “We showed that a clinically relevant dose of EZH2 inhibitor prior to bispecific antibody treatment did not impair T-cell efficacy and even enhanced memory T-cell expansion,” they reported.
The researchers found that EZH2 inhibition boosted these immunotherapies’ effects not just by making lymphoma cells more visible to them, but also by multiple other mechanisms, including reduction of immunosuppressive regulatory T cells (Tregs), and reprogramming of anticancer T cells in a way that makes their activity more durable. “Our findings reveal a critical role for EZH2 in modulating the immune landscape of FL and DLBCL,” the authors stated. “EZH2 inhibitors enhance immunotherapy by making lymphoma cells more immunogenic, reprogramming the TME, and boosting T-cell function.”
The team also confirmed that clinical trials are under way. “Based on our findings, two clinical trials have been initiated at Weill Cornell, one combining tazemetostat with standard-of-care CART19 in R/R B-NHL (NCT05934838), and another with mosunetuzumab in untreated FL (NCT05994235).”
In addition to their clinical trial-based work, the researchers are continuing to study how EZH2 inhibition boosts anticancer T cells, and this research could someday yield more precise therapeutic targets, said Béguelin, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.