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Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy...

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Autores principales: Sahoo, Prativa, Yang, Xin, Abler, Daniel, Maestrini, Davide, Adhikarla, Vikram, Frankhouser, David, Cho, Heyrim, Machuca, Vanessa, Wang, Dongrui, Barish, Michael, Gutova, Margarita, Branciamore, Sergio, Brown, Christine E., Rockne, Russell C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014796/
https://www.ncbi.nlm.nih.gov/pubmed/31937234
http://dx.doi.org/10.1098/rsif.2019.0734
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author Sahoo, Prativa
Yang, Xin
Abler, Daniel
Maestrini, Davide
Adhikarla, Vikram
Frankhouser, David
Cho, Heyrim
Machuca, Vanessa
Wang, Dongrui
Barish, Michael
Gutova, Margarita
Branciamore, Sergio
Brown, Christine E.
Rockne, Russell C.
author_facet Sahoo, Prativa
Yang, Xin
Abler, Daniel
Maestrini, Davide
Adhikarla, Vikram
Frankhouser, David
Cho, Heyrim
Machuca, Vanessa
Wang, Dongrui
Barish, Michael
Gutova, Margarita
Branciamore, Sergio
Brown, Christine E.
Rockne, Russell C.
author_sort Sahoo, Prativa
collection PubMed
description Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the Chimeric Antigen Receptor T-cell treatment Response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, proliferation, exhaustion, and persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parametrize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit.
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spelling pubmed-70147962020-02-15 Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data Sahoo, Prativa Yang, Xin Abler, Daniel Maestrini, Davide Adhikarla, Vikram Frankhouser, David Cho, Heyrim Machuca, Vanessa Wang, Dongrui Barish, Michael Gutova, Margarita Branciamore, Sergio Brown, Christine E. Rockne, Russell C. J R Soc Interface Life Sciences–Mathematics interface Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the Chimeric Antigen Receptor T-cell treatment Response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, proliferation, exhaustion, and persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parametrize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit. The Royal Society 2020-01 2020-01-15 /pmc/articles/PMC7014796/ /pubmed/31937234 http://dx.doi.org/10.1098/rsif.2019.0734 Text en © 2020 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Life Sciences–Mathematics interface
Sahoo, Prativa
Yang, Xin
Abler, Daniel
Maestrini, Davide
Adhikarla, Vikram
Frankhouser, David
Cho, Heyrim
Machuca, Vanessa
Wang, Dongrui
Barish, Michael
Gutova, Margarita
Branciamore, Sergio
Brown, Christine E.
Rockne, Russell C.
Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title_full Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title_fullStr Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title_full_unstemmed Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title_short Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
title_sort mathematical deconvolution of car t-cell proliferation and exhaustion from real-time killing assay data
topic Life Sciences–Mathematics interface
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014796/
https://www.ncbi.nlm.nih.gov/pubmed/31937234
http://dx.doi.org/10.1098/rsif.2019.0734
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