Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

Siqi Chen, Ping Xie, Matthew Cowan, Hao Huang, Horacio Cardenas, Russell Keathley, Edward J. Tanner, Gini F. Fleming, John W. Moroney, Alok Pant, Azza M. Akasha, Ramana V. Davuluri, Masha Kocherginsky, Bin Zhang, Daniela Matei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

BACKGROUND. Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study. METHODS. Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment. RESULTS. Among 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR. CONCLUSION. Epigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.

Original languageEnglish (US)
Article numbere158800
JournalJournal of Clinical Investigation
Volume132
Issue number14
DOIs
StatePublished - Jul 15 2022

ASJC Scopus subject areas

  • Medicine(all)

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