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 language | English (US) |
|---|---|
| Article number | e158800 |
| Journal | Journal of Clinical Investigation |
| Volume | 132 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2022 |
Funding
This research was supported by funding from the USAMRMC/ CDMRP (W81XWH170141, to DM and BZ); the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center (to DM); and the Walter S. and Lucienne Driskill Immunotherapy Research fund (to BZ). Astex Pharmaceuticals and Merck & Co. provided the drugs and funding for the clinical trial. Clinical trial coordination and statistical data analysis were performed through the Clinical Trial Office supported by National Cancer Institute (NCI), NIH grant CCSG P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. Tumor specimens were procured through the Pathology Core Facility (PCF) of Northwestern University, and sequencing was performed at the NUSeq Core, supported by NCI grant CCSG P30 CA060553. Flow cytometric analyses were performed at the North-western University Flow Cytometry Core Facility, which is supported by the Cancer Center Support Grant NCI CA060553. CyTEK analysis was performed by the Immunotherapy Assessment Core facility at Northwestern University. CyTOF analysis was conducted through the HIMC at Stanford University. This research was supported in part by the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. The authors would like to thank Kaitlyn O’Shea for her advice regarding statistical analysis. FUNDING. US Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.
ASJC Scopus subject areas
- General Medicine
