Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

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. Trial registration ClinicalTrials.gov NCT02901899. 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.

[1]  P. Laurent-Puig,et al.  Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. , 2022, Immunity.

[2]  M. Lauss,et al.  B Cells and Tertiary Lymphoid Structures: Friends or Foes in Cancer Immunotherapy? , 2021, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  James I. McDonald,et al.  Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner , 2021, Cancer Research.

[4]  B. Monk,et al.  Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. , 2021, The Lancet. Oncology.

[5]  D. Matei,et al.  Immunotherapy in ovarian cancer: we are not there yet. , 2021, The Lancet. Oncology.

[6]  David M. Woods,et al.  Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition , 2020, Journal for immunotherapy of cancer.

[7]  P. Hegde,et al.  High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade , 2020, Nature Medicine.

[8]  Hongyu Zhao,et al.  Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors , 2020, Nature Medicine.

[9]  Bin Zhang,et al.  OX40+ plasmacytoid dendritic cells in the tumor microenvironment promote antitumor immunity. , 2020, The Journal of clinical investigation.

[10]  G. Kristiansen,et al.  LAG3 (LAG-3, CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma , 2020, Journal for ImmunoTherapy of Cancer.

[11]  Jeffrey E. Lee,et al.  B cells and tertiary lymphoid structures promote immunotherapy response , 2020, Nature.

[12]  J. Wargo,et al.  B cells are associated with survival and immunotherapy response in sarcoma , 2020, Nature.

[13]  D. Schadendorf,et al.  Tertiary lymphoid structures improve immunotherapy and survival in melanoma , 2020, Nature.

[14]  K. Horimoto,et al.  CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy , 2019, Cancer Immunology Research.

[15]  D. Matei,et al.  A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer , 2019, Clinical Cancer Research.

[16]  G. Fisone,et al.  On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson’s Disease , 2019, Front. Neurosci..

[17]  G. Kochan,et al.  Functional systemic CD4 immunity is required for clinical responses to PD‐L1/PD‐1 blockade therapy , 2019, EMBO molecular medicine.

[18]  K. Kelly,et al.  Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial , 2019, JAMA oncology.

[19]  D. Matei,et al.  Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. , 2019, Gynecologic oncology.

[20]  Keith A. Crandall,et al.  Telescope: Characterization of the retrotranscriptome by accurate estimation of transposable element expression , 2018, bioRxiv.

[21]  A. Hotson,et al.  A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti–PD-(L)1 and Anti–CTLA-4 in Preclinical Models , 2018, Cancer Immunology Research.

[22]  S. Senju,et al.  Combined Blockade of IL6 and PD-1/PD-L1 Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment. , 2018, Cancer research.

[23]  B. Becher,et al.  Author Correction: High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy , 2018, Nature Medicine.

[24]  G. Kristiansen,et al.  Detailed analysis of adenosine A2a receptor (ADORA2A) and CD73 (5′-nucleotidase, ecto, NT5E) methylation and gene expression in head and neck squamous cell carcinoma patients , 2018, Oncoimmunology.

[25]  D. Matei,et al.  A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses , 2018, Clinical Cancer Research.

[26]  A. Kumanogoh,et al.  Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma , 2018, International immunology.

[27]  Fang Fang,et al.  Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs. , 2018, Cancer research.

[28]  C. Zahnow,et al.  Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden , 2017, Proceedings of the National Academy of Sciences.

[29]  E. Rock,et al.  Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. , 2017, The Lancet. Oncology.

[30]  Dana Pe’er,et al.  Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade , 2017, Cell.

[31]  Lirong Pei,et al.  Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers , 2017, Cancer Immunology Research.

[32]  T. Graeber,et al.  Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. , 2016, The New England journal of medicine.

[33]  C. Zahnow,et al.  Combining Epigenetic and Immunotherapy to Combat Cancer. , 2016, Cancer research.

[34]  Kathleen R. Cho,et al.  Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy , 2015, Nature.

[35]  J. Issa,et al.  Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. , 2015, The Lancet. Oncology.

[36]  M. Beckmann,et al.  Abstract B32: Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses , 2016 .

[37]  Trevor J Pugh,et al.  DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts , 2015, Cell.

[38]  Piet Demeester,et al.  FlowSOM: Using self‐organizing maps for visualization and interpretation of cytometry data , 2015, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[39]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[40]  S. Loi,et al.  Adenosine Receptor 2A Blockade Increases the Efficacy of Anti–PD-1 through Enhanced Antitumor T-cell Responses , 2015, Cancer Immunology Research.

[41]  D. Matei,et al.  TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells , 2014, Epigenetics.

[42]  R. Tibshirani,et al.  Automated identification of stratifying signatures in cellular subpopulations , 2014, Proceedings of the National Academy of Sciences.

[43]  D. Matei,et al.  Decitabine reactivated pathways in platinum resistant ovarian cancer , 2014, Oncotarget.

[44]  C. Batt,et al.  Epigenetic Potentiation of NY-ESO-1 Vaccine Therapy in Human Ovarian Cancer , 2014, Cancer Immunology Research.

[45]  S. Parmar,et al.  Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents , 2013, Leukemia.

[46]  Sean C. Bendall,et al.  viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia , 2013, Nature Biotechnology.

[47]  L. Salford,et al.  An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-γ: potential therapeutic use in autoimmune diseases. , 2012, Molecular immunology.

[48]  D. Matei,et al.  Epigenetic resensitization to platinum in ovarian cancer. , 2012, Cancer research.

[49]  Sean C. Bendall,et al.  Extracting a Cellular Hierarchy from High-dimensional Cytometry Data with SPADE , 2011, Nature Biotechnology.

[50]  Sean C. Bendall,et al.  Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum , 2011, Science.

[51]  T. Curiel,et al.  CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. , 2010, Cancer research.

[52]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[53]  Meng Li,et al.  Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer , 2009, BMC Medical Genomics.

[54]  K. T. Hogan,et al.  Treatment of ovarian cancer cell lines with 5-aza-2′-deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules , 2009, Cancer Immunology, Immunotherapy.

[55]  K. Odunsi,et al.  Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer , 2008, Clinical Cancer Research.

[56]  A. Ohta,et al.  A2A adenosine receptor protects tumors from antitumor T cells , 2006, Proceedings of the National Academy of Sciences.

[57]  Christian B. Woods,et al.  Analysis of repetitive element DNA methylation by MethyLight , 2005, Nucleic acids research.

[58]  K. Nephew,et al.  New anti-cancer strategies: epigenetic therapies and biomarkers. , 2005, Frontiers in bioscience : a journal and virtual library.

[59]  J. Issa,et al.  A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. , 2004, Nucleic acids research.

[60]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[61]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[62]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[63]  T. Choueiri,et al.  Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer , 2019 .

[64]  J. Cui,et al.  The Role of Tumor-Infiltrating B Cells in Tumor Immunity , 2019 .