Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783496710295650304 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7014796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sahooprativa mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT yangxin mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT ablerdaniel mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT maestrinidavide mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT adhikarlavikram mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT frankhouserdavid mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT choheyrim mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT machucavanessa mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT wangdongrui mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT barishmichael mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT gutovamargarita mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT branciamoresergio mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT brownchristinee mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata AT rocknerussellc mathematicaldeconvolutionofcartcellproliferationandexhaustionfromrealtimekillingassaydata |