Epigenetic priming enhances anti-tumor 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

doi:10.1172/JCI158800

Epigenetic priming enhances anti-tumor immunity in platinum resistant ovarian cancer

Siqi Chen,¹ Ping Xie,¹ Matthew Cowan,² Hao Huang,² Horacio Cardenas,² Russell Keathley,² Edward J. Tanner,³ Gini F. Fleming,⁴ John W. Moroney,⁴ Alok Pant,² Azza M. Akasha,⁵ Ramana V. Davuluri,⁶ Masha Kocherginsky,⁷ Bin Zhang,¹ and Daniela Matei²

Published June 7, 2022 - More info

View PDF

Abstract

BACKGROUND. Immune checkpoint inhibitors have modest activity in ovarian cancer (OC). To augment their activity, we used priming with a hypomethylating agent guadecitabine in a phase II study.

METHODS. Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and up to 5 prior regimens. Treatment was guadecitabine 30mg/m2 days 1-4, and pembrolizumab 200mg iv day 5, every 21 days. The primary endpoint was response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.

RESULTS. Among 35 evaluable patients, there were 3 partial responses (8.6%) and 8 (22.9%) patients with stable disease, resulting in clinical benefit rate (CBR) of 31.4% (95% CI: 16.9 – 49.3%). Median duration of clinical benefit was 6.8 months. Long-interspersed element-1 (LINE1) was hypomethylated in post-treatment PBMCs; methylomic and transcriptomic analyses showed activation of anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of naive and/or central memory CD4+ T cells, and of classical monocytes in patients with durable CBR. Higher baseline density of CD8+ T and CD20+ B cells and presence of tertiary lymphoid structures in tumors were associated with durable CBR.

CONCLUSION. Epigenetic priming using a hypomethylating agent with an immune check point inhibitor was feasible and induced durable clinical benefit associated to immune responses in selected patients with recurrent ovarian cancer.

TRIAL REGISTRATION. ClinicalTrials.gov registration number: NCT02901899.

FUNDING. 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), the Walter S. and Lucienne Driskill Immunotherapy Research funds (to BZ), Astex Pharmaceutical, Inc., Merck & Co., Inc., NCI CCSG P30 CA060553 (to the Robert H. Lurie Comprehensive Cancer Center), NCI CCSG P30 CA060553 (to NUSeq Core facility), NCI CA060553 (to NU Flow Cytometry Core Facility).

Epigenetic priming enhances anti-tumor immunity in platinum resistant ovarian cancer

Siqi Chen,¹ Ping Xie,¹ Matthew Cowan,² Hao Huang,² Horacio Cardenas,² Russell Keathley,² Edward J. Tanner,³ Gini F. Fleming,⁴ John W. Moroney,⁴ Alok Pant,² Azza M. Akasha,⁵ Ramana V. Davuluri,⁶ Masha Kocherginsky,⁷ Bin Zhang,¹ and Daniela Matei²

Article tools

Metrics

Go to

Epigenetic priming enhances anti-tumor immunity in platinum resistant ovarian cancer

Siqi Chen,1 Ping Xie,1 Matthew Cowan,2 Hao Huang,2 Horacio Cardenas,2 Russell Keathley,2 Edward J. Tanner,3 Gini F. Fleming,4 John W. Moroney,4 Alok Pant,2 Azza M. Akasha,5 Ramana V. Davuluri,6 Masha Kocherginsky,7 Bin Zhang,1 and Daniela Matei2

Article tools

Metrics

Go to

Sign up for email alerts

Siqi Chen,¹ Ping Xie,¹ Matthew Cowan,² Hao Huang,² Horacio Cardenas,² Russell Keathley,² Edward J. Tanner,³ Gini F. Fleming,⁴ John W. Moroney,⁴ Alok Pant,² Azza M. Akasha,⁵ Ramana V. Davuluri,⁶ Masha Kocherginsky,⁷ Bin Zhang,¹ and Daniela Matei²