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. 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 trimethylation at H3K27. 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 alteration of the epigenetic landscape may sensitize some tumors to checkpoint inhibitors.