ASH 2024 | Combining EZH2 and HDAC inhibition to prime immunotherapy for B-cell lymphomas

I’m very excited to talk about an oral presentation here at ASH that was presented by a postdoc in my lab, Ted Piorczynski. This is a project that we’ve been working on looking at the combination of EZH2 plus HDAC inhibition as a way to prime immunotherapy. As you know, germinal-centered B-cell lymphomas often evade the immune system. They have recurrent epigenetic mutations that down-regulate MHC expression, leading to decreased antigen presentation and recognition by our immune milieu. So by using EZH2 inhibitors and HDAC inhibitors, we’re able to up-regulate MHC1 and 2 on the surface of the cells. We’re also actually able to increase CD19 and 20 expression, allowing for better engagement with bispecific antibodies. And we were able to evaluate this in cell lines as well as human lymphoma peripheral blood on a clinical trial. Then looked at the combination of these two drugs as priming for bispecific antibody mosunetuzumab. In this way, we looked at co-cultures of healthy peripheral blood T-cells with B-cell lymphoma cell lines and found that priming with EZH2 and HDAC inhibitors allowed for better cell kill when combined with bispecific antibodies and healthy T-cells. Furthermore, we then developed organoids and looked at diffuse large B-cell lymphoma organoids and infiltration of healthy T-cells in the presence of dual epigenetic therapy and bispecifics and found that when combined, we’re able to induce increased cell kill and increased interaction between the B and T-cells. So we’re really excited about this project. We do have a clinical trial ongoing now combining EZH2 and HDAC inhibition, and we’re hoping that we’ll be able to learn more about this interaction and modulating the immune response so that we can better prime therapy with bispecifics and really deepen the responses there so potentially have more curative effects perhaps in diseases like follicular lymphoma and better effect in diffuse large B-cell lymphoma.

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