Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative poorly differentiated chordoma after EZH2 inhibition and radiotherapy Journal Article
| Authors: | Gounder, M. M.; Zhu, G.; Roshal, L.; Lis, E.; Daigle, S. R.; Blakemore, S. J.; Michaud, N. R.; Hameed, M.; Hollmann, T. J. |
| Article Title: | Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative poorly differentiated chordoma after EZH2 inhibition and radiotherapy |
| 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 immunofluo-rescence analysis. Results: We report an exceptional and durable response (2þ 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 þ T cells, FoxP3 þ 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. © 2019 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 7 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-04-01 |
| Start Page: | 2064 |
| End Page: | 2071 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-3133 |
| PUBMED: | 30642912 |
| PROVIDER: | scopus |
| PMCID: | PMC9165752 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
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