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Restoring lymphoma immunosurveillance by combined EZH2 inhibition and immunotherapy

Roberta Zappasodi

Roberta Zappasodi

PhD

Joan & Sanford I. Weill Medical College of Cornell University

Project Term: October 1, 2021 - June 30, 2024

The project builds on evidence that mutations leading to persistent EZH2 activation drive germinal center B-cell lymphomagenesis by disrupting T-cell surveillance, and will test the hypothesis that EZH2 inhibition synergizes with immune checkpoint blockade and/or co-stimulation to eradicate these diseases. These results will provide the rationale for clinical development of precision-medicine immune-epigenetic combination therapies for lymphomas where these mechanisms are specifically altered.

Lay Abstract

The treatment of B-cell non-Hodgkin lymphomas (B-NHLs) remains challenging, with many patients dying of these diseases. Recent advanced immunotherapies have revolutionized the treatment of many malignancies; however, B-NHLs are largely refractory to these new therapies. The heterogeneity of B-NHLs suggests that the treatment of these diseases may benefit from more personalized precision-medicine approaches, targeting specific molecular alterations that drive lymphoma development in each patient. Mutations leading to activation of the gene repressor enzyme EZH2 are frequent in B-NHLs originating in germinal centers of peripheral lymphoid organs (GCB-NHLs), which are highly refractory diseases. These mutations induce lymphoma development by making GCB-NHL cells invisible to the immune system via downregulation of critical receptors for the interaction with immune cells. EZH2 inhibitors (EZH2i) are approved for the treatment of follicular lymphoma (a subset of GCB-NHLs). These drugs have shown to both reduce lymphoma proliferation/survival and to increase the expression of receptors for the interaction between lymphoma and immune cells. These observations suggest that EZH2i may help restore the anti-lymphoma immune response and underscore the potential of combining EZH2i with immunotherapy to improve the treatment of GCB-NHLs. In support of this new combination therapy approach, our preliminary results indicate that: 1. EZH2i enhance the recruitment of inflammatory immune cells into EZH2-mutant B-cell lymphomas in mice; 2. EZH2 represents a target of dysfunctional T lymphocytes, and, accordingly, EZH2i decrease these dysfunctional immune cells, which can in turn favor the activation of anti-tumor immune responses; 3. Specific forms of immunotherapies – either blockade of immune checkpoints (“immune breaks”) or activation of immune co-stimulatory receptors (“immune accelerators”) – can promote the immune-mediated control of lymphoma. Our hypothesis is that combining EZH2i with immunotherapy will increase the therapeutic efficacy against GCB-NHLs by restoring the interactions between lymphoma and immune cells for the recognition and killing of lymphoma by immune cells. We will test this hypothesis by evaluating the anti-lymphoma activity of available EZH2i in combination with immune checkpoint blockade (anti-PD-1 and anti-CTLA-4) and immune co-stimulatory therapies (CD40 and GITR agonist antibodies) using genetically engineered mouse lymphoma models, which faithfully reproduce human EZH2-mutant GCB-NHLs. We will validate the clinical relevance of these combination therapies by examining the expression of the above immunotherapy targets in lymphoma biopsies collected from patients before and after treatment with EZH2i.

Program
Translational Research Program
Grant Subprogram
TRP Basic
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