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Research Article| Volume 156, ISSUE 1, P222-232, January 2020

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An autologous humanized patient-derived-xenograft platform to evaluate immunotherapy in ovarian cancer

  • Sarah B. Gitto
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Hyoung Kim
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Stavros Rafail
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Dalia K. Omran
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Sergey Medvedev
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Yasuto Kinose
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Alba Rodriguez-Garcia
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Ahron J. Flowers
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Haineng Xu
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Lauren E. Schwartz
    Affiliations
    Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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  • Author Footnotes
    1 Authors contributed equally.
    Daniel J. Powell Jr.
    Correspondence
    Corresponding author. University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Smilow CTR, Office 8-103, Philadelphia, PA, 19104-5156, USA.
    Footnotes
    1 Authors contributed equally.
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally.
    Fiona Simpkins
    Correspondence
    Corresponding author. University of Pennsylvania, 3400 Civic Center Blvd, South Tower, Suite 10-176, Philadelphia, PA, 19104-5156, USA..
    Footnotes
    1 Authors contributed equally.
    Affiliations
    Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally.
Published:December 06, 2019DOI:https://doi.org/10.1016/j.ygyno.2019.10.011
An autologous humanized patient-derived-xenograft platform to evaluate immunotherapy in ovarian cancer
Previous ArticleCDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer
Next ArticleA TGF-β associated genetic score to define prognosis and platinum sensitivity in advanced epithelial ovarian cancer

      Highlights

      • •
        Patient-matched orthotopic PDX/TIL models were developed and validated.
      • •
        TILs with autologous tumor reactivity were successfully expanded from donor HGSOC for infusion.
      • •
        TILs co-cultured with autologous tumor cells exhibited HLA-dependent IFNγ production and activation.
      • •
        Combination TILs and anti-PD-1 significantly increased patient-matched tumor cell lysis and increased survival in vivo.

      Abstract

      Objective

      The aim of this study was to “humanize” ovarian cancer patient-derived xenograft (PDX) models by autologous transfer of patient-matched tumor infiltrating lymphocytes (TILs) to evaluate immunotherapies.

      Methods

      Orthotopic high-grade serous ovarian cancer (HGSOC) PDX models were established from three patient donors. Models were molecularly and histologically validated by immunohistochemistry. TILs were expanded from donor tumors using a rapid expansion protocol. Ex vivo TIL and tumor co-cultures were performed to validate TIL reactivity against patient-matched autologous tumor cells. Expression of TIL activation markers and cytokine secretion was quantitated by flow cytometry and ELISA. As proof of concept, the efficacy of anti-PD-1 monotherapy was tested in autologous TIL/tumor HGSOC PDX models.

      Results

      Evaluation of T-cell activation in autologous TIL/tumor co-cultures resulted in an increase in HLA-dependent IFNγ production and T-cell activation. In response to increased IFNγ production, tumor cell expression of PD-L1 was increased. Addition of anti-PD-1 antibody to TIL/tumor co-cultures increased autologous tumor lysis in a CCNE1 amplified model. Orthotopic HGSOC PDX models from parallel patient-matched tumors maintained their original morphology and molecular marker profile. Autologous tumor-reactive TIL administration in patient-matched PDX models resulted in reduced tumor burden and increased survival, in groups that also received anti-PD-1 therapy.

      Conclusions

      This study validates a novel, clinically relevant model system for in vivo testing of immunomodulating therapeutic strategies for ovarian cancer, and provides a unique platform for assessing patient-specific T-cell response to immunotherapy.

      Keywords

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      Article info

      Publication history

      Published online: December 06, 2019
      Accepted: October 9, 2019
      Received in revised form: October 9, 2019
      Received: March 9, 2019

      Identification

      DOI: https://doi.org/10.1016/j.ygyno.2019.10.011

      Copyright

      © 2019 Elsevier Inc. All rights reserved.

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