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The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory

View ORCID ProfileJeffrey West, Mark Robertson-Tessi, Kimberly Luddy, Derek S. Park, Drew F.K. Williamson, Cathal Harmon, Hung T. Khong, Joel Brown, View ORCID ProfileAlexander R.A. Anderson
doi: https://doi.org/10.1101/349142
Jeffrey West
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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  • For correspondence: jeffrey.west@moffitt.org alexander.anderson@moffitt.org
Mark Robertson-Tessi
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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Kimberly Luddy
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FloridaSchool of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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Derek S. Park
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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Drew F.K. Williamson
Translational Hematology and Oncology Research, Cleveland Clinic Foundation
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Cathal Harmon
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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Hung T. Khong
Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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Joel Brown
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FloridaDepartment of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA
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Alexander R.A. Anderson
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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  • ORCID record for Alexander R.A. Anderson
  • For correspondence: jeffrey.west@moffitt.org alexander.anderson@moffitt.org
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Abstract

An upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 ER+breast cancer combines an aromatase inhibitor and a PD-L1 checkpoint inhibitor, and aims to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We develop a mathematical model of the essential components of the PEPI score in order to identify successful combination therapy regimens that minimize both tumor burden and metastatic potential, based on time-dependent trade-offs in the system. We consider two molecular traits, CCR7 and PD-L1 which correlate with treatment response and increased metastatic risk. We use a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded into an ecological model of tumor population growth dynamics. The resulting model predicts both evolutionary and ecological dynamics that track with changes in the PEPI score. We consider various treatment regimens based on combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was found to be a 1 month kick start of the immune checkpoint inhibitor followed by five months of continuous combination therapy. Relative to a protocol with both therapeutics given together from the start, this delayed regimen results in transient sub-optimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final five months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 18, 2018.
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The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory
Jeffrey West, Mark Robertson-Tessi, Kimberly Luddy, Derek S. Park, Drew F.K. Williamson, Cathal Harmon, Hung T. Khong, Joel Brown, Alexander R.A. Anderson
bioRxiv 349142; doi: https://doi.org/10.1101/349142
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The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory
Jeffrey West, Mark Robertson-Tessi, Kimberly Luddy, Derek S. Park, Drew F.K. Williamson, Cathal Harmon, Hung T. Khong, Joel Brown, Alexander R.A. Anderson
bioRxiv 349142; doi: https://doi.org/10.1101/349142

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