Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy. uri icon

Overview

abstract

  • 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.Patient and Methods: 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.

publication date

  • January 14, 2019

Research

keywords

  • Chordoma
  • Enhancer of Zeste Homolog 2 Protein
  • Immunomodulation
  • SMARCB1 Protein

Identity

Scopus Document Identifier

  • 85064161852

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-18-3133

PubMed ID

  • 30642912

Additional Document Info

volume

  • 25

issue

  • 7