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Model-dependent GD2 upregulation in Ewing sarcoma with the EZH2 inhibitor tazemetostat: Prerequisites for combination
Lara Bücker1, Bianca Altvater1, Jutta Meltzer1
1University Children's Hospital Muenster.
Abstract:
The disialoganglioside GD2 is a cell surface marker of neuroblastoma and an attractive target for chimeric antigen receptor (CAR) T-cell therapy. GD2 is also expressed in Ewing sarcoma (EwS), but more heterogeneously and often below the threshold required for CAR-mediated T-cell activation. We previously showed that pharmacological inhibition of the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2), for example with the approved drug tazemetostat, selectively upregulates GD2 expression in EwS cells in vitro. Here, we evaluated prerequisites for combining EZH2 inhibition with GD2-directed CAR T-cell therapy. Oral tazemetostat induced GD2 expression in EwS xenografts in vivo, but the effect was model-dependent and not consistently reproducible. In vitro analyses revealed a pronounced impact of EZH2 inhibition on CAR T cell biology. Tazemetostat markedly impaired T cell proliferation and expansion, while enhancing antigen-specific cytolytic activity on a per-cell basis. In contrast, tazemetostat did not measurably affect macrophage polarization under conditions promoting M2-like phenotypes characteristic of the EwS tumor microenvironment. Together, these findings argue against concomitant administration of tazemetostat with GD2-specific CAR T cells. The variable target induction capacity of tazemetostat in vivo and its recent withdrawal from the market limit the translational potential of the strategy. Systematic in vivo screening of epigenetically active compounds may identify more suitable candidates for robust, clinically relevant modulation of GD2 expression in EwS and other GD2-positive cancers.
Insights
Combining EZH2 inhibition with GD2 CAR T-cell therapy for Ewing sarcoma is not recommended. Tazemetostat
Area of Science:
- Immunology
- Oncology
- Epigenetics
Background:
- Disialoganglioside GD2 is a target for neuroblastoma and Ewing sarcoma (EwS) CAR T-cell therapy.
- GD2 expression in EwS is heterogeneous and often insufficient for CAR T-cell activation.
- EZH2 inhibition, using tazemetostat, can upregulate GD2 in EwS cells.
Purpose of the Study:
- To evaluate combining EZH2 inhibition with GD2-directed CAR T-cell therapy for EwS.
- To assess tazemetostat's effects on GD2 expression and CAR T-cell function in vivo and in vitro.
Main Methods:
- Administered oral tazemetostat to EwS xenografts in vivo.
- Analyzed GD2 expression in EwS cells and xenografts.
- Evaluated tazemetostat's impact on CAR T-cell proliferation, expansion, and cytolytic activity in vitro.
- Assessed effects on macrophage polarization.
Main Results:
- Oral tazemetostat induced GD2 expression in EwS xenografts, but with model-dependent and inconsistent reproducibility.
- Tazemetostat impaired T-cell proliferation and expansion but enhanced per-cell cytolytic activity.
- Tazemetostat did not significantly affect macrophage polarization towards M2-like phenotypes.
Conclusions:
- Concomitant administration of tazemetostat with GD2-specific CAR T cells is not advised.
- Variable in vivo target induction and tazemetostat's market withdrawal limit clinical potential.
- Further screening of epigenetic compounds is needed for robust GD2 modulation in EwS and other GD2-positive cancers.
