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Clinical MedicineIn-Press PreviewImmunologyOncology Open Access | 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

1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Chen, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Department of Obstetrics and Gynecology, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Chicago, Chicago, United States of America

5Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University, Chicago, United States of America

6Department of Biomedical Informatics, Stony Brook University, New York, United States of America

7Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

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Published June 7, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI158800.
Copyright © 2022, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 7, 2022 - Version history
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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).

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