IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52528-7.html
   My bibliography  Save this article

Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial

Author

Listed:
  • Marina Baretti

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Ludmila Danilova

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Jennifer N. Durham

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Courtney B. Betts

    (Oregon Health & Science University
    Akoya Biosciences)

  • Leslie Cope

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Dimitrios N. Sidiropoulos

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins)

  • Joseph A. Tandurella

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Soren Charmsaz

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Nicole Gross

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Alexei Hernandez

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Won Jin Ho

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Chris Thoburn

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Rosalind Walker

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • James Leatherman

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Sarah Mitchell

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Brian Christmas

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Ali Saeed

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University)

  • Daria A. Gaykalova

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center
    University of Maryland School of Medicine)

  • Srinivasan Yegnasubramanian

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins
    Johns Hopkins Medicine)

  • Elana J. Fertig

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins
    Johns Hopkins University)

  • Lisa M. Coussens

    (Oregon Health & Science University)

  • Mark Yarchoan

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins)

  • Elizabeth Jaffee

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins)

  • Nilofer S. Azad

    (Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
    Johns Hopkins University
    Bloomberg-Kimmel Institute at Johns Hopkins)

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA.

Suggested Citation

  • Marina Baretti & Ludmila Danilova & Jennifer N. Durham & Courtney B. Betts & Leslie Cope & Dimitrios N. Sidiropoulos & Joseph A. Tandurella & Soren Charmsaz & Nicole Gross & Alexei Hernandez & Won Jin, 2024. "Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52528-7
    DOI: 10.1038/s41467-024-52528-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52528-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-52528-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sanjeev Mariathasan & Shannon J. Turley & Dorothee Nickles & Alessandra Castiglioni & Kobe Yuen & Yulei Wang & Edward E. Kadel III & Hartmut Koeppen & Jillian L. Astarita & Rafael Cubas & Suchit Jhunj, 2018. "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells," Nature, Nature, vol. 554(7693), pages 544-548, February.
    2. Beth A. Helmink & Sangeetha M. Reddy & Jianjun Gao & Shaojun Zhang & Rafet Basar & Rohit Thakur & Keren Yizhak & Moshe Sade-Feldman & Jorge Blando & Guangchun Han & Vancheswaran Gopalakrishnan & Yuanx, 2020. "B cells and tertiary lymphoid structures promote immunotherapy response," Nature, Nature, vol. 577(7791), pages 549-555, January.
    3. Florent Petitprez & Aurélien Reyniès & Emily Z. Keung & Tom Wei-Wu Chen & Cheng-Ming Sun & Julien Calderaro & Yung-Ming Jeng & Li-Ping Hsiao & Laetitia Lacroix & Antoine Bougoüin & Marco Moreira & Gui, 2020. "B cells are associated with survival and immunotherapy response in sarcoma," Nature, Nature, vol. 577(7791), pages 556-560, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jia Wei & Xiaofeng Lu & Qin Liu & Yao Fu & Song Liu & Yang Zhao & Jiawei Zhou & Hui Chen & Meng Wang & Lin Li & Ju Yang & Fangcen Liu & Liming Zheng & Haitao Yin & Yang Yang & Chong Zhou & Ping Zeng &, 2023. "Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Nanda Horeweg & Hagma H. Workel & Dominik Loiero & David N. Church & Lisa Vermij & Alicia Léon-Castillo & Ricki T. Krog & Stephanie M. Boer & Remi A. Nout & Melanie E. Powell & Linda R. Mileshkin & He, 2022. "Tertiary lymphoid structures critical for prognosis in endometrial cancer patients," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Mattia Rediti & Aranzazu Fernandez-Martinez & David Venet & Françoise Rothé & Katherine A. Hoadley & Joel S. Parker & Baljit Singh & Jordan D. Campbell & Karla V. Ballman & David W. Hillman & Eric P. , 2023. "Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Akshay J. Patel & Zena N. Willsmore & Naeem Khan & Alex Richter & Babu Naidu & Mark T. Drayson & Sophie Papa & Andrew Cope & Sophia N. Karagiannis & Esperanza Perucha & Gary W. Middleton, 2022. "Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Olivia Le Saux & Maude Ardin & Justine Berthet & Sarah Barrin & Morgane Bourhis & Justine Cinier & Yasmine Lounici & Isabelle Treilleux & Pierre-Alexandre Just & Guillaume Bataillon & Aude-Marie Savoy, 2024. "Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Li Yuan & Guo-Dong Jia & Xiao-Fei Lv & Si-Yi Xie & Shan-Shan Guo & Da-Feng Lin & Li-Ting Liu & Dong-Hua Luo & Yi-Fu Li & Shen-Wen Deng & Ling Guo & Mu-Sheng Zeng & Xiu-Yu Cai & Sai-Lan Liu & Xue-Song , 2023. "Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Yoshito Yamada & Tuan Thanh Nguyen & Daniela Impellizzieri & Katsutaka Mineura & Rintaro Shibuya & Alvaro Gomariz & Martina Haberecker & Jakob Nilsson & César Nombela-Arrieta & Wolfgang Jungraithmayr , 2023. "Biased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Jieqiong Liu & Ying Wang & Zhenluan Tian & Ying Lin & Hengyu Li & Zhaowen Zhu & Qiang Liu & Shicheng Su & Yinduo Zeng & Weijuan Jia & Yaping Yang & Shengqiang Xu & Herui Yao & Wen Jiang & Erwei Song, 2022. "Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Brian S. White & Aurélien Reyniès & Aaron M. Newman & Joshua J. Waterfall & Andrew Lamb & Florent Petitprez & Yating Lin & Rongshan Yu & Martin E. Guerrero-Gimenez & Sergii Domanskyi & Gianni Monaco &, 2024. "Community assessment of methods to deconvolve cellular composition from bulk gene expression," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    10. Matthew T. Campbell & Surena F. Matin & Alda L. Tam & Rahul A. Sheth & Kamran Ahrar & Rebecca S. Tidwell & Priya Rao & Jose A. Karam & Christopher G. Wood & Nizar M. Tannir & Eric Jonasch & Jianjun Ga, 2021. "Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    11. Zhenzhen Xun & Xinyu Ding & Yao Zhang & Benyan Zhang & Shujing Lai & Duowu Zou & Junke Zheng & Guoqiang Chen & Bing Su & Leng Han & Youqiong Ye, 2023. "Reconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Jae-Won Cho & Seyeon Park & Gamin Kim & Heonjong Han & Hyo Sup Shim & Sunhye Shin & Yong-Soo Bae & Seong Yong Park & Sang-Jun Ha & Insuk Lee & Hye Ryun Kim, 2021. "Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    13. Yang Liu & Shuang-Yan Ye & Shuai He & Dong-Mei Chi & Xiu-Zhi Wang & Yue-Feng Wen & Dong Ma & Run-Cong Nie & Pu Xiang & You Zhou & Zhao-Hui Ruan & Rou-Jun Peng & Chun-Ling Luo & Pan-Pan Wei & Guo-Wang , 2024. "Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    14. David Hsiehchen & Muhammad S. Beg & Radhika Kainthla & Jay Lohrey & Syed M. Kazmi & Leticia Khosama & Mary Claire Maxwell & Heather Kline & Courtney Katz & Asim Hassan & Naoto Kubota & Ellen Siglinsky, 2024. "The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    15. Lenka Kasikova & Jana Rakova & Michal Hensler & Tereza Lanickova & Jana Tomankova & Josef Pasulka & Jana Drozenova & Katerina Mojzisova & Anna Fialova & Sarka Vosahlikova & Jan Laco & Ales Ryska & Pav, 2024. "Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    16. Jianming Xu & Yi Li & Qingxia Fan & Yongqian Shu & Lei Yang & Tongjian Cui & Kangsheng Gu & Min Tao & Xiuwen Wang & Chengxu Cui & Nong Xu & Juxiang Xiao & Quanli Gao & Yunpeng Liu & Tao Zhang & Yuxian, 2022. "Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    17. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. Phillip B. Nicol & Danielle Paulson & Gege Qian & X. Shirley Liu & Rafael Irizarry & Avinash D. Sahu, 2024. "Robust identification of perturbed cell types in single-cell RNA-seq data," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    20. Hong Yuen Wong & Quanhu Sheng & Amanda B. Hesterberg & Sarah Croessmann & Brenda L. Rios & Khem Giri & Jorgen Jackson & Adam X. Miranda & Evan Watkins & Kerry R. Schaffer & Meredith Donahue & Elizabet, 2022. "Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52528-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.