Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 inhibition and radiotherapy

Purpose: We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor and followed by radiotherapy. Experimental Design: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC and employed a novel methodology of multiplex immunofluorescence analysis. Results: We report an exceptional and durable response (2+ years) in a patient with SMARCB1 deleted, metastatic, poorly differentiated chordoma; a lethal disease with an overall survival of 6 months. The patient was treated for 4 weeks with tazemetostat, an EZH2 inhibitor in a phase II clinical trial. At the time of progression she underwent radiation to the primary site and unexpectedly had a complete response at distant metastatic sites. We evaluated baseline and on-treatment tumor biopsies and demonstrate that tazemetostat resulted in pharmacodynamic inhibition of EZH2 as seen by decrease in histone methylation at H3K27me3. Tazemetostat resulted in a significant increase in intratumoral and stromal infiltration by proliferative (high Ki-67), CD8+ T cells, FOxP3+ regulatory T cells and immune cells expressing checkpoint regulators PD-1 and LAG-3. These changes were pronounced in the stroma. Conclusions: These observations are the first demonstration in patient samples confirming that EZH2 inhibition can promote a sustained antitumor response that ultimately leads to T cell exhaustion and checkpoint activation. This suggests that targeted altering of the epigenetic landscape may sensitize some tumors to checkpoint inhibitors

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