Journal
GYNECOLOGIC ONCOLOGY
Volume 156, Issue 1, Pages 222-232Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2019.10.011
Keywords
Ovarian cancer; Patient derived xenograft; Tumor infiltrating lymphocytes; Anti-PD-1
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Funding
- Penn Ovarian Cancer Translational Center of Excellence at the Abramson Cancer Center
- Ovarian Cancer Research Center
- Ovarian Cancer Research Alliance
- Rivkin Center for Ovarian Cancer
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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 IFN gamma production and T-cell activation. In response to increased IFN gamma production, tumor cell expression of PD-LI 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. (C) 2019 Elsevier Inc. All rights reserved.
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