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Destabilization of CAR T-cell treatment efficacy in the presence of dexamethasone

View ORCID ProfileAlexander B. Brummer, Xin Yang, Eric Ma, View ORCID ProfileMargarita Gutova, Christine E. Brown, View ORCID ProfileRussell C. Rockne
doi: https://doi.org/10.1101/2021.10.01.462697
Alexander B. Brummer
1Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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  • For correspondence: abrummer@coh.org
Xin Yang
2Department of Hematology and Hematopoietic Cell Translation and Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Eric Ma
2Department of Hematology and Hematopoietic Cell Translation and Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Margarita Gutova
3Department of Stem Cells and Leukemia, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Christine E. Brown
2Department of Hematology and Hematopoietic Cell Translation and Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Russell C. Rockne
1Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Abstract

Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, Dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and Dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and Dexamethone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a non-autonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of Dexamethasone. Using time as a bifurcation parameter, we show that (1) the presence of Dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells and (2) as Dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of Dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of Dexamethasone in patients.

Author summary Bioengineering and gene-editing technologies have paved the way for advance immunotherapies that can target patient-specific tumor cells. One of these therapies, chimeric antigen receptor (CAR) T-cell therapy has recently shown promise in treating glioblastoma, an aggressive brain cancer often with poor patient prognosis. Dexamethasone is a commonly prescribed anti-inflammatory medication due to the health complications of tumor associated swelling in the brain. However, the immunosuppressant effects of Dexamethasone on the immunotherapeutic CAR T-cells are not well understood. To address this issue, we use mathematical modeling to study in vitro dynamics of Dexamethasone and CAR T-cells in three patient-derived glioblastoma cell lines. We find that in each cell line studied there is a threshold of tolerable Dexamethasone concentration. Below this threshold, CAR T-cells are successful at eliminating the cancer cells, while above this threshold, Dexamethasone critically inhibits CAR T-cell efficacy. Our modeling suggests that in the presence of Dexamethasone reduced CAR T-cell efficacy, or increased exhaustion, can occur and result in CAR T-cell treatment failure.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† rrockne{at}coh.org

Copyright 
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 4.0 International license.
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Posted October 01, 2021.
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Destabilization of CAR T-cell treatment efficacy in the presence of dexamethasone
Alexander B. Brummer, Xin Yang, Eric Ma, Margarita Gutova, Christine E. Brown, Russell C. Rockne
bioRxiv 2021.10.01.462697; doi: https://doi.org/10.1101/2021.10.01.462697
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Destabilization of CAR T-cell treatment efficacy in the presence of dexamethasone
Alexander B. Brummer, Xin Yang, Eric Ma, Margarita Gutova, Christine E. Brown, Russell C. Rockne
bioRxiv 2021.10.01.462697; doi: https://doi.org/10.1101/2021.10.01.462697

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